The Ester Enolate Claisen Rearrangement: I. Stereochemical Control Through Stereoselective Enolate Formation. II. Construction of the Prostanoid Skeleton Citation Willard, Alvin Keith (1976) The Ester Enolate Claisen Rearrangement: I. Stereochemical Control Through Stereoselective Enolate Formation. II. Construction of the Prostanoid Skeleton. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/FX8A-9T58. https://resolver.caltech.edu/CaltechTHESIS:12042017-161832975 Abstract Part I: The [3,3]-sigmatropic rearrangement of a number of allylic esters 1, as the enolate anions of the corresponding silyl ketene acetals, produces the γ,δ-unsaturated acids 2 in 66 - 88% yield. The mild conditions allow rearrangement of acid sensitive and thermally labile esters. Rearrangement of ester 1g affords (E)-4-decenoic acid (2g) with greater than 99% stereoselectivity. (E)-Crotyl propanoate (12) leads to erythro-acid 14 when enolization is carried out in THF, but to the threo-acid 15 when the solvent is 23% HMPA-THF. Results with a variety of esters demonstrate that kinetic enolization with lithium diisopropylamide gives selective formation of the geometrical enolate H in THF and the isomeric enolate I in HMPA-THF. Similar results are obtained with 3-pentanone. (Scheme I) Part II: A convergent synthesis of the prostaglandin skeleton is described. The ester enolate modification of the aliphatic Claisen rearrangement is used to form the key C 8 -C 12 bond. Rearrangement of ester 18 provides the lactone 29 which is converted to the prostanoid 30. Similarly, the lactone 52, a potential intermediate in the synthesis of 12-methyl PGA 1 , is obtained from ester 51. Preparation of ester 51 features Claisen rearrangement of ester 38, which leads to the dienoate 41 after desulfenylation. Model studies of reduction of γ,δ-epoxy-α-β-unsaturated esters to δ-hydroxy-β,γ-unsaturated esters are described. This reduction is accomplished with lithium in ammonia at -78° for conversion of epoxy ester 50 to ester 51. (Scheme II) Scheme I: Refer to pdf for formulas Scheme II: Refer to pdf for formulas Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Ireland, Robert E. Thesis Committee: Unknown, Unknown Defense Date: 26 August 1975 Funders: Funding Agency Grant Number NSF UNSPECIFIED NIH UNSPECIFIED Caltech UNSPECIFIED Record Number: CaltechTHESIS:12042017-161832975 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:12042017-161832975 DOI: 10.7907/FX8A-9T58 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 10582 Collection: CaltechTHESIS Deposited By: Benjamin Perez Deposited On: 05 Dec 2017 16:57 Last Modified: 24 Aug 2024 00:05 Thesis Files Preview PDF - Final Version See Usage Policy. 35MB Repository Staff Only: item control page

THE ESTER ENOLATE CLAISEN REARRANGEMENr I. Stereochemical Control Through Stereoselective Enolate Fonnation II. Construction of the Prostanoid Skeleton Thesis by Alvin K. Willard In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1976 (Submitted August 26, 1975) ii to bill weber who got me started to carla who kept me going iii when life gives you lemons make lemonade iv Acknowledgements I thank Professor Robert E. Ireland for his guidance for the past few years and for his interest in my career. Some of the work described here was done by Dr. Richard Mueller of the Far North; I am grateful for the opportunity to work with him. Special thanks go to other members of The Group for the stimulation, advice, encouragement and enjoyment that they provided. I thank the National Science Foundation, the National Institutes of Health and the California Institute of Technology for financial support. Finally, I thank the Division of Chemistry and Chemical Engineering for providing a stimulating environment. v Abstract Part I: The ~,iJ -sigmatropic rearrangement of a m.unber of allylic esters 1, as the enolate anions or the corresponding silyl ketene acetals, IV - produces the y,o-unsaturated acids 2 in 66 - 88% yield. The mild conditions allow rearrangement of acid sensitive and thermally labile esters. Rearrangement of ester }j affords (.£)-4-decenoic acid (~) with greater than 99% stereoselectivity. (E)-Crotyl propanoate (12) ,.., leads to erythro-acid 1J when enolization is carried out in TI-IF, but to the threo-acid 15 when the solvent is 23% HMPA-'IBF. """' Results with a variety of esters demonstrate that kinetic enolization with lithium diisopropylamide gives selective formation of the geometrical enolate Jl in TIIF and the isomeric enolate l., in HMPA-TIIF. obtained with 3-pentanone. Similar results are (Scheme I) Part II: A convergent synthesis of the prostaglandin skeleton is described. The ester enolate modification of the aliphatic Claisen rearrangement is used to form the key Ca-Cu bond. Rearrangement of ester JJ provides the lactone #"\/ 29 which is converted to the prostanoid 'V 30. Similarly, the lactone ~' a potential intermediate in the synthesis of 12-methyl PGA 1 , is obtained from ester~· Preparation of ester~ features Claisen rearrangement of ester "38, which leads to the dienoate 'V 41 after J vi desulfenylation. t.bdel studies of reduction of y,o-epoxy-a,8-unsaturated esters to o-hydroxy-8,y-unsaturated esters are described. This reduction is accomplished with lithium in amnonia at -78° for conversion of epoxy ester ~ to ester ~· (Scheme II) Scheme I: Rs R1t RI R2 ~ OH 2 1 ,...., ~ ~CH, . H (o/CH Clh OH 3 14 "" O)('H3 0 RO HMPA-'IHF CH3 RO\__/H H XO \_/ " XO H ~ " I ~ CH 3 vii Scheme II: 0 52 ......... - - - 1.~ . CH 3 0 38 41 viii Table of Contents Page Title Page 1 Acknowledgements iv Abstract v Part I 1 Discussion 2 Experimental Section . 25 References and Notes 47 Part II . . . . . 51 Discussion . 52 Experimental Section . 68 Referen~es and Notes Propositions 102 106 Abstract of Propositions 107 Proposition 1 108 Proposition 2 111 Proposition 3 114 PrOJ!OSition 4 117 Proposition 5 120 1 PART I Stereochemical Control Through Stereoselective Enolate Fonnation 1 2 Consideration of possible synthetic approaches to prostanoids suggested a convergent scheme which would incorporate the connection of a "top-half" and a "bottom-half" as a key step in the synthesis. Further analysis indicated that the required carbon-carbon bond could be generated by Claisen rearrangement of a properly designated sub strate. This rearrangement would also result in the correct number of suitably functionalized carbon atoms for subsequent generation of the cyclopentanone ring system. In order to take complete advantage of the convergence inherent in this scheme, the efficient use of both "halves" of the molecule rn this key step was essential. The most popular procedures for the aliphatic Claisen rearrangement--vinyl ether, 2 ortho ester, 3 and amide acetal~--were not acceptable because of their use of one of the reaction partners in excess. These considerations led us to investi- gate the possibility that enolate anions derived from allyl esters would undergo a similar ~,j -sigrnatropic rearrangement. Conceptually, this ester enolate Claisen rearrangement offered two major advantages. Connection of the two hydrocarbon fragments would be accomplished by ester formation. Such a reaction could be carried out in high yield under mild conditions and would require only equivalent amounts of either component. The generation of the required 1,5-diene system would occur through enolization under basic conditions rather than with the acid catalysis required in the vinyl ether 2 and ortho ester 3 rearrangements. These basic reaction condi- tions would be compatible with a variety of functional groups. 3 Base catalyzed rearrangement of a few allyl esters had been observed. 5 The special nature of the esters, the harshness of the conditions, and the low yields severely limited the usefulness of this procedure as a general synthetic transformation. A solution for these problems became apparent as a result of investigations by Rathke 6 which provided a method for the quantitative generation of ester enolates free from competing aldol-type condensation reactions . Indeed, the application of these methods to a variety of allyl esters resulted in enolate anions and/or the corresponding trimethylsilyl ketene acetals which underwent Claisen rearrangement under surprisingly mild conditions. 7 Further development of these reaction conditions was necessary to avoid fragmentation of the enolate anions themselves and C-silylation by trimethylchlorosilane (TMSCi). 7 The use of tert-butyldimethylchlorosilane (TBSC1) 8 in the presence of hexamethylphosphor amide (HMPA) to trap the enolates afforded excellent yields of the corresponding silyl ketene acetals and the procedure presented here (see experimental section) appears to be quite general (TABLE I). The advantage of the basic reaction conditions is demonstrated by the rearrangement of the ester lj which would be impossible under - the acidic conditions of the vinyl ether and ortho ester rearrangements . An additional advantage in the use of TBSCl is worthy of note. - The silyl esters (~., 3j) which result from rearrangement are sufficiently stable to permit isolation, but can be conveniently and mildly transformed into a variety of other functional groups, - -- - -- -- la lb le ld le lf -. lg lh -. li lj lk - Ester H CH3 CH3 CH3 CH 3 !!_-CGH13 H H !!_-CGH1 3 !!_-CGH13 CH3 Ri - H H CH3 CH3 (E) -C2HsCH=CH CH 3 H CH3 (~ -C2HsCH=CH !!_-C3H7 n-C4H9 R2 R3 1 O?-R' H H H CH3 H H H CGHsS H H Br R3 H H H !!_-CsH11 !!_-CsH11 H H H H H H R4 H H H H H CH3 H H CH 30 CH30 H Rs OH ~ O~ 2 R R3 R'*R' Rs Claisen Rearrangement of Allyl Ester Enolates R'~R' Rs - TABLE I. a soc 7ld D 77C 83 88 71 66 70 75 (7 5) 80(78) 69 Yield(%)b c c c c B B A(B) A(B) A A Procedure 2 ...... ~ 5 Footnotes to TABLE I. a A= rearrangement as the enolate anion prepared with LICA; B= rearrangement as the trimethylsilyl ketene acetal; C= rearrangement as the tert.-butyldimethylsilyl ketene acetal; D= rearrangement as the tert.-butyldimethylsilyl ketene acetal prepared by reaction of the a-bromo ester with Zn and TBSCl in 'IHF-HMPA. b Yield of acid after hydrolysis of the silyl ester. c Yield of methyl ester prepared by cleavage of silyl ester with KF in HMPA followed by alkylation of carboxylate anion with iodomethane. d R3 = H in the product acid. 6 including alkyl esters (e.g., 4). - - ..... OTBS 1) KF,KHC03 The temperatures required for the rearrangement itself are quite mild in comparison with the temperatures in excess of 100° which are required for the generation of, or the rearrangement of, the 1,5-diene system for the alteTilative procedures mentioned above. A few approximate half-lives (TABLE II) serve to demonstrate the remarkable ease with which the rearrangement occurs as well as a few effects of structure on reactivity. A distinct advantage of this facile rearrangement is that esters whose structure permits the possibility of competing thermal reactions can be employed in the rearrangement. For instance, no problem of Cope rearrangement of the -- silyl ester 3i generated in the rearrangement of li is encountered . ....._. OTES I I/ • 7 TABLE II. Half-Lives for Rearrangement of Silyl Ketene Acetals at 32°a Ketene Acetal b t~ (min)c ~ 210 ± 30 t: Ketene Acetalb t~ (min)c ~CH3 Q~l\N\.CH3 5 ± 1 OTMS - - 4a 4c ~CH; ~ OTMS 150 ± 30 ((<:' .& «l 3 H3 OTMS - - 4b 4d -n-CsH11~ r~ o'( 6 ± 1 <l OTBS 4g ,,._ 4h a Not isolated but generated in situ as described in TABLE I and experimental section. b TMS = (CH 3) 3Si; TBS=tert.-Bu (CH3)2Si. c By NMR analysis of silicon methyl region as described in experimental section. 8 An alternative approach to silyl ketenc acetals is demonstrated in the rearrangement of ester lk. ~ 'The reaction of this a-bromo ester with zinc and TBSCl in TI-IF-HMPA generates the required silyl ketene acetal under quite mild conditions, and the rearrangement procee<ls with the usual facility. 9 Metho:xy substituted allyl alcohol synthons such as 9 employed in ""'"' - - the esters li and lj have proven to be highly useful in the synthesis of cyclopentanone derivatives 7 ' 10 an<l deserve further comment. 1ne 2-alkoxy-a, S-unsaturated esters such as R arc re<Jdi I y ""'- available by the Wittig synthesis developed by Grell anJ Machlei<lt 11 (SCHEME I). This procedure results in approximately a 1:1 mixture of..§__- to ~-isomers which may be carried through the rearrangment sequence or separated by silica gel chromatography. Reduction by lithium aluminum hydride gives cleanly the allylic alcohols 9 which """' - can be converted to stable esters such a lj under a variety of non-acidic reaction conditions. In the course of the Claisen rearrangement, both a new carboncarbon double bond and a new carbon-carbon single bond arc fonne<l. To assess further the synthetic utility of the transfonnation, the stereochemical outcome at both of these sites was investigated. Ample theoretical considerations 1 ?. and experimental evidence 3 ' 13 - 17 on various ~' ~ -sigma tropic rearrangements indicate quite clearly that, in the absence of any unusual steric constraints, the rearrangement proceeds through a chair-like transition state. An examination of non-bonded interactions readily indicates which of the - two possible transition states A or B will be favored. ~ 111e equatorial 9 SQIEME I. H~ CH 1 3 6 0 ""-- -'\,, NaH + LiAlH + THF THF 0 OCH3 (Et0)2ij_!H-C02CH3 -- - 8-E 7 9-Z ,,.. - (CH -(CH,J),o + 0 lj - _7:._ + 3 - Pyridine o)('/' 9-E "'- - 0 lj -!i ...._ 10 - disposition of R puts transition state B at lower energy which results in predominant f ormation of the E-double bond. 17 R~ H y c B A "'" Not surprisingly, this predominance is found for the ester enolate Claisen rearrangement as well. The rearrangement of ester - - lg leads to the acid 2g with greater than 99% stercoselectivity. Similar observations have been made by Katzenellenbogen 18 who finds greater than 98% stereoselectivity for formation of the E-trisubsti- - tuted double bond in acid 11. _!!-CsHuyH, 83% _!!-C,Hn'Q >99 .5% E OH lg Zg ...... CH3 n-C,H1~ - 80% ~-CGH13 ~ >99% E OYH3 OH 10 ..,,.,.. 11 11 A second consequence of the chair-like transition state is that the stereochemistry about the newly fonned carbon-carbon single bond can be predicted from the geometries of the double bonds in the starting 1,5-diene system. Although a priori it was not obvious that enolization would result in selective formation of one of the two isomeric enolates, the stereochemical consequence of rearrangement of either enolate isomer is predictable. 14 - 16 - Silyl ketene acetal ....... D (x = TBS) will give the acid F, while E will lead only to acid G. "'" ,,..... Similar arguments can be made for esters containing a cis-double bond in the allylic alcohol fragment. H XO D """ H E G Rearrangement of (E)- and (Z)-crotyl propanoate (12 and 13) was used """' """' to probe the stereochemical outcome of enolization (SCHEME II). 12 The data in TABLE III demonstrates the unanticipated effect of solvent polarity on the ratio of erythro 14 to threo 15 products """"' ........ obtained. in the rearrangement. WhenQ§)-crotyl propanoate (12) is enolized in tetrahydrofuran (TI-IF) and allowed to rearrange as either the enolate anion or the derived silyl ketene acetal, selective form- - ation of the erythro-acid 14 is observed. When the more coordinating solvent system, 23% HMPA-11-IF is employed, enolization takes an alter- - nate course and the threo-acid 15 predominates. ~}crotyl Rearrangement of propanoate (13) gives the expected complete reversal of ....... product ratios and verifies that the product determining step is indeed enolization. These results indicate that in TI-IF the Z-type enolate H is ""'" preferentially formed and trapped but when the solvent is 23% HMPATI-IF, enolization leads to the geometrically isomeric E-type enolate anion I. As was mentioned above, rearrangement of the enolate anion is only preparatively useful in specific cases. Only the enolate anion formed in TI-IF from(I}crotyl propanoate (12) rearranges in good yield. - ~ The low yields obtained with the other enolate anions probably reflect variable activation energies for rearrangement 15 and the known reactivity of ester enolates at temperatures above -78°. 7 ' 8 It is worthy of note, however, that the enolate anions show no tendency to interconvert. To evaluate these initial observations and to determine the generality of the process, the synthetically more interesting esters lj were examined under similar conditions .....- (SCHEME III and TABLE IV). 13 SCHEME II. 14 HMPA-THF 15 - 13 R~H RO\---./CH, XO~ xc/\CH3 I H ~ ~ X = Li, TBS Conditionsa Anion Ketene Acetal Anion Ketene Acetal Anion Ketene Acetal Anion Ketene Acetal 12 _.... 1HF 1HF HMPA-TIIF HMPA-TIIF IBF IBF HMPA-IBF HMPA-IBF Solventb 75 86 79 21 73 6 75 Yield(%)c 86/J4 92/8 87/13 13/87 19/81 25/ 75 11/ 89 - --14/15d - 1HF=l00% TIIF; HMPA-IBF=23 vol% HMPA-1HF. e The geometrical enolate which would lead to the predominate product assuming a chair-like transition state. d Determined by glpc analys i s of methyl esters as described in experimental section. c Isolated and distilled. b I H H H H I I Enola tee a The rearrangement was carried out as the enolate anion (Anion) or this anion was quenched with TBSCl before rearrangement (Ketene Acetal). 13 - 13 -1212 -13 13 ....... 12 ......... - - Effect of Solvent on Rearrangement of©- and @-Crotyl Propanoate (12 and 13). Ester TABLE III. ~ ,...... 15 In this case the derived silyl esters were cleaved with potassilUil fluoride in HMPA 19 and the resulting carboxylate salts were esterified with methyl iodide. 20 Analysis of the mixture of methyl esters by NMR indicated that again the same stereoselectivity pertained. The isomeric products were easily separated by silica gel chromatography, but the stereochemistry could not be unambiguously assigned from the spectral data. The assignment in TABLE IV and SCHEME III is based on the outcome of experiments with crotyl propanoates 12 and 13. """"" This stereoselectivity is even more general. ,,.,.... The silyl kctene acetals obtained by trapping simple ester enolates with TBSCl can be isolated in quantitative yield. 8 When this procedure i s used to study the enolization of a variety of esters, a high degree of selectivity for formation of one enolate in THF and the isomeric enolate in HMPA-THF is observed in nearly every case (TABLE V). Only methyl - phenylacetate (18b), in wh i ch the enolate is stabilized by conjugation with an aromatic ring, does not exhibit the changeover i n stereoselectivity. Again, the stereochemistry of the kctenc acctals - - 19 and 20 cannot be deduced from the spectral data (sec TABLE VT) and is assigned by comparison with the results from the crotyl propanoates - 12 and 13 (TABLE III and SCHEME II) and for 3-pcntanone (vide infra). The question quickly arises whether these r esults apply only to esters or whether the selective formation of either geometrical enolate of ketones is poss i ble. The symmetrical ketone, 3-pentanone , in which no problem of rcgioselectivity arises, was chosen for study. Again, a high degree of selectivity for one enolate in TI-Ir and the other in HMPA-THF was observed (TABLE V). The silyl enol ethers were 16 SCHEME III. THF HMPA-THF THF - lj-~ 17 TABLE IV. -- -- 68 57 59 69 88/12 20/80 21/79 85/15 -- Yield(%)d Major Isomer 16/17c 1HF=l00% IBF; HMPA-1HF=23 vol% HMPA-IBF . d After chromatographic separation. c From~ analysis of methyl esters. b a Rearranged as the silyl ketene acetal (TBS); converted to methyl esters as described in experimental section. -- lj-E lj-E -- -- TifF -llj-I j-Z HMPA-IBF 1HF HMPA-IBF Solventb Ester Effect of Solvent on Rearrangement of (Z} and $}2-Methoxy-2-nonenyl Pentanoate (lj-Z and lj-E). a '-] I-' 1 C2Hs C2Hs C6Hs C6Hs (Gl3)3C (Gl3)3 C C2Hs C2Hs 3-Pentanone 3-Pentanone R quant. yield 19 - OR 1 Gl3 Gl3 013 Gl3 Gl3 Gl3 (Gl 3) 3c (Gl3) 3c R1 H HMPA-THF THF HMPA-THF THF HMPA-THF 1HF THF HMPA-THF THF HMPA -THF 20 - 19/20c 91/9 16/84 29/71 5/95 97/3 9/91 95/5 23/77 77 /23d,e 5/95d , e -- OR 1 ">===<OTBS Solventb H)=={TB: R Effect of Structure on Ratio of Enolates.a e b By NMR or VPC analysis. ~TB~ H CH 2-CH 3 a Enolization with 1.1 equiv LDA at - 78 ° , trapped with TBSCl, HMPA. THF = 100% THF, HMPA-THF = 23 vol % HJl.1PA -THF. c By NMR analysis of isolated mixture. d Ratio represents : CH3\,__/H2cy cH>==< OTBS --- - 18a 18a 18b 18b 18c 18c 18d 18d -- 18 """"' Ester RCH2C02R TABLE V. 00 ...... R C2Hs C2Hs CGHs CGHs (o-I3)3C (o-I3)3C C2Hs C2Hs ----3.72(t)b 3.43(t)c 4. 72(s) 4.60(s) 3.7S(s) 3.37(s) 3.88(t)d 3.90(t)d 8 vinyl H 0.18(s) 0.12(s) 0. 30(s) 0. 23(s) 0.18(s) O.lS(s) O.lS(s) 0.12(s) o GhSi 0.9S(s) 0.92(s) l.02(s) 1.00(s) 0.9S(s) 0.93(s) 0.92(s) 0.90(s) o (o-I 3)3CSi = 6.8 Hz. d J = 7 Hz. c J J = 7. 2 Hz. 3.SS(s) 3.4S(s) 3.73(s) 3.67(s) 3.52(s) 3.43(s) l.32(s) 1. 2S(s) 8 R1 b --7. 3 (m) 7.3(m) 1. 06 (s) 1.10 (s) --- oR 10% solution in CDC1 3, internal standard a-IC1 3 , chemical shifts in ppm downfield from U.1S. Gf3 Q-f3 Gf3 Gf3 Gl3 Gf3 (a-I3) 3C (a-I3) 3C R1 a - --- 19a 20a 19b 20b 19c 20c 19d 20d - - NMR Data for Silyl Ketene Acetals 19 and 20.a Ketene Acetal TABLE VI. \.0 ~ 20 easily separated by VPC and readily identified by NMR (see Experimental Section). 21 , 22 The unambiguous stereochemistry rn this case reinforces the assignments for the esters above (TJ\l3L1: V). In order to gain further insight about the mechanism, methyl butanoate (18a) was subjected to enolization and trapping Wlder a variety of conditions. The results recorded in TABLE VII point out - a smooth change from one enolate (19a) with no HMPA present to predominately the other (20a) as the amount of HMPA increases to the point of saturation. There is no discrete molar quantity which effects the changeover in stereoselectivity. The kinetic nature of the stereoselectivity is supported by the fact that the enolate formed in THF maintains its integrity in the presence of IJiv1PA (entry 2) and that the silyl ketene acetal fonned in TilF is stable for at least two hours in the reaction medium at 67° (entry 1). When the enolization is carried out in HMPA-11-IF, the trapping agent (TBSCl) may be present during the enolization or added afterward with no change in the outcome (entries 6 and 7). It appears that the observed stereoselectivity results from the kinetic enolization of esters and ketones, and that this cnolization takes a different course as a function of the solvent employed. One explanation for this dramatic solvent effect may lie in an analysis of the steric requirements for enolization. Two transition states J When the solvent is the less-coordinating THF, the interaction of the carbonyl and K leading to the two enolates can be imagined. oxygen with the lithium cation must be quite important, and the carbonyl oxygen becomes effectively bulkier than OR: The resulting 1. 2. 3. 4. 5. 6. 7. 0 0 0.5 1.0 2.0 4.7 8 4.7 8 Equiv. HMPAb a Enolized with 1.1 equiv LDA in 0.3 M solution. b Based on LDA. c By ~1R analysis. d No change after heating ketene acetals in reaction medilllTI for 2 hr at 67°. ~ -~- 18a H H 85/15 89/11 53/47 23/77 16/84 16/84f 91/9d 19a/20ac ........... ......- 20a OCH3 + C2H')===(OTBS e Following enolization, 4.7 equiv f-:IJ\!PA added, stirred for 4 min at -78° then quenched with TBSCl. f A mixture of TBSCl and ester added to LDA solution. g This quantity of HMPA is not entirely soluable at -78°. 100% TI-IF 100% TI-IFe 3% HMPA-TI-IF 6% HMPA-IBF 11% HMPA-1HF 23% HMPA-TI-IF 23% ]{\lPA-IBF Solvent 19a ~ OTBS C2HsHCH3 Effect of HMPA concentration on Ester Enolate Isomer Ratio. a C2HsCH2C02CH3 TABLE VII. N ....... 22 non-bonded interactions would bestow a higher activation energy on transition state K and enolization would be expected to proceed ""' through transition state J. The presence of HMPA, on the other hand , .A. RlfOR' ... >-;· / J Li H K ""' should result in a greater degree of solvation of the lithium cation and an enhanced reactivity of the amide base. The lithium - c.::1rhonyl oxygen interaction should be much weaker and transition s tate K, ~ in which R becomes eclipsed with the now sterically smaller carbonyl oxygen during enolization, should be favored. This degree of control over the stereochemistry of the 1,5-diene unit enormously expands the potential of the es ter enolate Claisen rearrangement and provides the synthetic chemist with a powerful weapon with which to attack the problem of stercochcmistry of acyclic molecules. The ability to generate selectively the <lesired stereo - chemistry in the rearranged products reganlless of the stcrcochemi s try present in the starting material pl aces this modification i n a unjquc 23 position among procedures for the aliphatic Claisen rearrangement. The stereochemical outcome of the vinyl ether rearrangement has been investigated by Schmid 15 who notes a preponderance of the cis-propenyl ether ......... 21 from the reaction of crotyl alcohol with propanal in the presence of phosphoric acid. A similar result was obtained in a study of the amide acetal rearrangement by Sucrow and Richter. 16 In this case a strong preference for fonnation of the z- - configuration 24 of the intermediate ketenc O,N-acctal was inferred - from the stereochemistry of the rearrangement products. The opposite stereochemistry of the ketene acetal portion of the molecule has been obtained by requiring this double bond to lie in a ring (e.g., ......... 28) . - Cyclic ortho esters such as 26 have been successfully employed in this approach by Lythgoe. 23 As well as extending the utility of the Claisen rearrangement, these results have general implications in other synthetic reactions. Recent reports have related enolate geometry to intennolecu1ar reactions including aldol con<lcnsation 2 ''- 26 tions. 27 and alkylation reac- The rapidly increasing use of ketone and ester enolatcs as versatile intermediates in organic synthesis will lill<loubtedly unveil more of these relationships. The complementary conditions which have been described here for stereoselective enolization should find useful application in these areas as well. 24 SGIEME IV. ~H3 CH3 OH+ ~3 CH3CH2CHO VH ~CH3 + - ~H - ~CH, ~CH 3 ~CH 3 OH )~(' + ~~H3 21 78% + ~(CH3)2 CH3-CH=C N(CH 3) 2 'oCH3 - -23 26 _._ 24 95% - 27 3 22 22% N(CH 3 ) 2 25 5% """"" 25 Experimental Section 26 CY.2-Buten-1-ol (~-Crotyl Alcohol). 1be following procedure gave the most consistent results. A solution of 7.0 g (0.1 mol) of 2-butyn-1-ol in 75 ml of methanol containing 500 mg of 5% Pd/BaS0 4 and 5 ml of ~-collidine was stirred rapidly under 1 atm of hydrogen until 2440 ml (0.1 mol) of hydrogen was absorbed (2.25 hr). 1be reaction mixture was filtered with the aid of celite, and the filtrate was subjected to fractional distillation through a 30-cm vacuumjacketed Vigreux collmlJl. The pot was maintained at ll0° while the pressure was gradually lowered. Most of the methanol distilled at atmospheric pressure, with an additional portion d.istilling as the pressure was lowered to 90 mm. After a small forenm at this pressure, the material distilling at 72-80° (90 mm) was collected. amounted to 5.6 g (78%). 1bis Analysis by VPC 26 (100° and 150°, !-4'' x 8' 10% Carbowax 20 M, 60 ml/min, thermocouple) indicated that this material consisted of cis-crotyl alcohol contaminated with 1% methanol, 1% ~-collidine and less than 1% trans-crotyl alcohol. A similar reaction without s-collidine gave cis-crotyl alcohol containing 12% trans-crotyl alcohol and 10% n-butanol. Methyl ®-2-Methoxy-2-nonenoatc (8-!l); Methyl @-2-Methoxy- 2r nonenoate (8-~). To a mechanically stirred suspension of sodium hydride (mineral oil-free) in SO ml of dry TI-IF was added dropwise over 30 min, 8.0 g (33.3 mmol) of methyl d.iethoxyphosphinylmcthoxyacetate 11 (7). """ The mixture was stirred for an additional 4S min at 25° and then cooled to o0 • During 30 min, the reaction mixture was 26 treated with 3.8 g (33.3 rrnnol) of heptanal (6) in 5 ml of dry 'IlIF .A. while vigorous stirring was maintained. addition a gurrnny precipitate formed. Toward the end of the The reaction mixture was allowed to warm to 25° and stirring was continued for 2 hr. After cautious addition of 25 ml of water, the product esters were isolated by ether extraction. 29 The slightly brown liquid residue was subjected to evaporative distillation at 45° (0.08 nun) and gave 5. 7 g css ·:.) of the unsaturated esters. NMR analysis indicated that this was approx- imately a 1:1 mixture of double bond isomers. Separation of the isomers was accomplished by medium-pressure chromatography 28 of 2.0 g of the mixture on 2.5 x 50 on of silica gel with 3% ether/petroleum ether at a flow rate of 2 ml/min. of the Z-isomer .,... 8-Z. - Elution with 930 ml gave 686 mg An analytical sample was prepared by evaporative distillation at 45° (0.08 mm): NMR (CDC1 3 ) 83.66 (s, 3H, ether 01 3 ) , 3.78 (s, 3H, ester CH 3 ) , 6.29 (t, lH, J = 7.5 Hz, vinylic II); ir (CHC1 3 ) 1720 (C = 0), 1645 (C = C), 1430, 1275, 1090 cm Anal. Calcd for C11 H20 0 3 : C, 65.97; H, 10.07. - l found: C, 65.99; H, 10.03. Further elution with 120 ml of the same solvent system gave 245 mg of a mixture of the Z-and E-isomers. Continued elution with 990 ml of this solvent system gave 797 mg of the E-isomer 8-E. ~- An analytical sample was prepared by evaporative distillation at 45° (0.08 nun): NMR (CDC1 3 ) 83.62 (s, 3H, ether 01 3 ) , 3.83 (s, 3H, ester CH 3 ) , 5.37 (t, lH, J = 7 .5 Hz, vinylic H); ir (CHC1 3 ) 1720 (C = 0), 1635 (C = C), 1435, 1370, 1240, 1145 cm H, 10.05. -1 . 27 Lithililll Allilllinlilll Hydride Reduction of Esters 8. A solution of 380 mg (10.0 rrrrnol) of lithium allilllinlilll hydride rn 40 ml of dry ether was cooled to 0°. This solution was subjected to the dropwise addition of 2.5 g (12.5 nnnol) of either the.£- or E-ester ~-.£or~-_£ in 5 ml of dry ether over 30 min. The cooling bath was removed and the reaction mixture was stirred at 25° for 1 hr. Following this, dropwise addition of 2 ml of ethyl acetate effected destruction of excess hydride. Work-up according to the Fieser procedure 30 afforded 2.1 g (quantitative crude yield) of a colorless oil. A portion of this material was purified by medililll-pressure chromatography 28 on 1.25 x 50 cm of silica gel with 60% ether/petrolelilll ether at a flow rate of 1 ml/min. Elution with 100 ml gave a colorless oil (90%). J\n analyt- ical sample was prepared by evaporative distillation at 50° (0.08 mm). _£-2-Methoxynon-2-enol (]_-_D: NMR (CDC1 3 ) 63.66 (s, 3H, CH 3 0), 4.10 (br s, 2H, -CH 2 0-), 4. 75 (t, HI, J = 7 Hz, vinylic H); ir (CHCl 3 ) 3650-3400 (OH), 1675 (C = C), 1460, 1150, 1080, 885 cm Anal. Calcd for C10 H20 0 2 : C, 69. 72; H, 11. 70. - I Found: C, 69. 70; H, 11.67 . .£-2-Methoxynon-2-enol Ci_-§): NMR (CDC1 3 ) 63. 55 (s, 311, Cll 3 0-), 4.16 (br s, 2H, -CH 2 0-), 4.54 (t, lH, J = 7.5 Hz, vinylic H); ir (CHC1 3 ) 3590 and 3450 (OH), 1670 (C = C), 1225, 1120, 1055, 1015 crn- 1 Anal. Calcd for C10 H20 0 2 : H, 11. 59. C, 69.72; H, 11.70. Found: C, 69.57; 28 Pre£aration of AllXl Esters. A. From the Aci<l Chlori<le. The following esters were prepared by reaction of 1.0 equiv of the allylic alcohol 3l _ with 1. 0 equiv of the required acid chlori<le 3 2 in the presence of 1.1 equiv of pyridine as an 0.3 M solution in dry dichloromethane: (E}2-Butenyl Propanoate (12). Yield 92%, bp 65-68° (35 rrnn): :A NMR (CDCb) ol.13 (t, 3H, J = 7.5 Hz, CH 3 ) , 1.72 (<l, 31-1, .J = 5 llz, vinylic CH 3 ) , 2.34 (q, 2H, J = 7.5 Hz, -0-1 2C = 0), 4.52 (<l, 21-1, J= 6Hz, -CH 20-), 5.70 (m, 2, vinylicH's). ~2-Butenyl Propanoate (13). Yield 86%, bp 76-79° (60 nnn): NMR (CDC1 3 ) 61.13 (t, 3H, .J = 7.5 Hz, CH 3 ) , 1.72 (d, 3H, J = 5 llz, vinylic CH 3 ) , 2.34 (q, 2H, J = 7.5 Hz, -CH2C = 0), 4.65 (<l, 2H, J = 5 Hz, -CH 20-), 5. 70 (m, 2H, vinylic I-I's). ~ethyl-2-nonenyl Propanoate (lf). Yield 63%, bp 75° (0.5 nun): NMR (CDC1 3 ) ol.65 (br s, 3H, vinylic Cll 3 ) , 1.97 (m, 211, vinylic Cll 2 ), 2.35 (q, 2H, J = 7 Hz, -CH 2C0 2 - ) , 4.47 (br s, 2H, -CH/)-), 5.45 (hr t, lH, vinylic H); 1015, 940 cm -1 ir (CHC1 3 ) 1727 (C = 0), 1380, 1345, 1280, 1185, 1085, • Anal. Calcd for C13 H24 0 2 : C, 73.54; H, 11.39. Found: C, 73.42; H, 11.35. l-He:xyl-2-propenyl 2-(Phenylthio)propanoate (lh). evaporatively distilled at ll0° (0.05 rrnn): Yield 88 %, NMR (CDC1 3 ) c;l.53 (<l, 31!, J = 7 Hz, CH 3 ) , 3.87 (q, lH, J = 7Hz, -CHS-), 5.3 (m, 4H, Cll2 =CIHJl-0-), 7.33 (m, SH, phenyl); 930 cm - l . ir (O-IC1 3 ) 1725 (C = 0), 1380, 1260, 1165, 985, 29 Anal. Calcd for C11H2 4 02S: Folllld: C, 69.82; H, 8.27; S, 10.96. C, 69.90; H, 8.35; S, 10.89. (6}-2-Methoxy-2-nonenyl Pentanoate (lj-~. distilled at 60° (0.003 nun): Yield 78%, evaporatively NMR (CDC1 3) 03.60 (s, 3H, 01 30), 4.57 (s, ZH, -01 20-), 4.86 (t, lH, J = 7 Hz, vinylic H); ir (01Cl 3 ) 1725 (C = 0), 1675 (C = C), 1460, 1165, 960 cm- 1 • Anal. Calcd for C1sH2s03: C, 70.27; H, 11.01. Found: C, 70.31 ; H, 11.03. Q?)-2-Methoxy-2-nonenyl Pentanoate (lj-S). Yield 91%, evaporatively ~ distilled at 60° (0.006 nun): NMR (CDC1 3) 03.53 (s, 3H, CH 30), 4.62 (s, 2H, -0120-), 4.65 (t, lH, J = 7 Hz, vinylic H). 1 (C = 0), 1670 (C = C), 1260, 1170, 1070 on- . Anal. Calcd for C1sH2s03: C, 70.27; H, 11.01. ir (CHC1 3) 1730 Fol.Uld: C, 70.35; H, 10.84. 2-Butenyl 2-Bromohexanoate (lk~. distilled at 50° (0.05 nun): Yield 98%, evaporatively NMR (CDCl3) 01.73 (d, 3H, J = 5 Hz, vinylic CH 3), 4.20 (t, lH, J = 7 Hz, -CHBr), 4.60 (d, 2H, J = 5 Hz, -0120-), 5.7 (m, 2H, vinylic H's); ir (01Cl 3) 1735 (C = 0), 1380, 1150, 970 cm -1 . Anal. Calcd for C1oH11Br02: H, 6.76. C, 48.21; H, 6.88; Found: C, 48.40; 30 B. From the i;:-Nitrophenyl Ester. Esters of E-3-hexenoic acid were prepared by reaction of 1.0 equiv of the alcohol in dry triethylamine solution with 1.0 equiv of E_-nitrophenyl _§_-3-hexenoate, which was prepared as foll ows: A solution of 10 rnmol of E_-nitrophenyl tri- fluoroacetate in 6 ml of dry triethylamine was cooled to 0° and treated with 10 mmol of 3-hexenoic acid. This mixture was stirred for 30 min Benzene extraction 29 including a base wash at 0° and 30 min at 25°. afforded E_-nitrophenyl _§_-3-hexenoate as an orange oil: NMR (CDC1 3) ol.02 (t, 3H, J = 7, CH 3 ) , 2.13 (m, 2H, -CH2 -), 3.32 (d, 2H, J = 5 Hz , CH2), 5.68 (m, 2H, -CH=CH-), 7.32 (d, 2H, J = 9 Hz, aromatic), 8.30 (d, 2H, J = 9 Hz, aromatic). The following esters were prepared in this manner: 2-Butenyl €)-3-Hexenoate (le) . Yield 43%, bp 70-72° (2 nnn): NMR (CDC1 3) ol . 00 (t, 3H, J = 7 Hz, CH 3), 1.72 (d, 3H, J = 5 Hz, vinylic CH 3 ) , 2.03 (m, 2H, vinylic CH 2), 3.03 (d, 2H, J = 5 Hz, -CH 2C0 2-), 4.53 (d, 2H, J = 5 Hz, -CH 2 0-), 5.63 (m, 4H, vinylic H's); ir (CHC1 3) 1728 (C = 0), 1685, 1380, 1170, 965 an- 1 • Anal . Calcd for C10 H16 0 2 : C, 71.39; H, 9.59. Found: C, 71.35; H, 9.53. (!}2-Methoxy-2-nonenyl(E}3-Hexenoate (li-f). evaporatively distilled at 65° (0.002 mm): Yield 31%, NMR (CDC1 3) 03.05 (m, 2H, -CH2C02-), 3.60 (s, 3H, CH30), 4.57 (s, 2H, -CH20-), 4.87 (t, lH , J = 7 Hz, -CH=C-0-), 5.53 (m, 2H, -CH=CH-); ir (CHC13) 1728 (C = 0), 1675, 1460, 1155, 970 an - 1 . Anal. Calcd for C16 H28 0 3: H, 10.55. C, 71 .60; H, 10.52. Found: C, 71.64 31 @-2-Methoxy-2-nonenyl @3-Hexenoate (li-£). evaporatively distilled at 60° (0.006 nun): Yield 65%, NMR (CDC1 3 ) 63.05 (d, 2H, J = 5 Hz, -CH 2C02-), 3.52 (s, 3H, CH 3 0), 4.62 (s, 2H, -CH 20-), 5.57 (m, 2H, -CH=CH-); ir (CHC1 3 ) 1728 (C = 0), 1670, 1465, 1160, 970 an Anal. Calcd. for C16 H28 0 3 : C, 71.60; H, 10.52. Found: - l C, 71.61; H, 10.66. Claisen Rearrangement of Esters la-£ (TABLE I). Enolate Anion. A. As the A stirred solution of 1.70 g (12 .1 nmol) of dry ~isopropylcyclohexylamine in 20 ml of dry 11IF was cooled to o0 and treated with 5.0 ml (11.1 rrunol) of ~-butyl lithium in hexane solution over several minutes. After the mixture was stirred for an additional 10 min following the addition, the solution was cooled to -78° and --- 10 nnnol of the appropriate ester (la-f) was added dropwise over 2-3 min. After an additional 2 min, the cooling bath was removed and the reaction mixture was allowed to warm to 25°. This solution was stirr ed for the indicated period of time, and then the reaction mixture was poured into 20 ml of 5% aqueous sodium hydroxide solution. The aqueous solution was washed with two 15-ml portions of ether (washings discarded), acidified with cone hydrochloric acid, and then the product acid was isolated by dichloromethane extraction. 29 Distillation at reduced pressure afforded the pure acid in the indicated yield (TABLE I). 32 B. As the Tr:imethrlsilzl Ketene Acetal. The esters la-f (TABLE I) were enolized at -78° as described in A previously. Within 5 min after the addition of the ester was complete, 1. 2 g (11.1 nunol) of TMSCl was added in one batch. The cooling bath was then removed and the reaction mixture was allowed to warm to 25° over 30 min. Stirring at either 25° or 67° was continued as indicated for each particular ester. Following this, 3 ml of methanol was added and the reaction mixture was stirred for 10 min at 25° to effect hydrolysis of the silyl ester. The reaction mixture was then added to 20 ml of 5% aqueous sodilllTl hydroxide solution and the product was isolated as described in A. The distilled acids prepared by this procedure con- tained 1-2 rnol % 2-tr:imethylsilyl-substitute<l acid. This impurity could be removed as described below. 4-Pentenoic Acid (2a). 2 hr at 67°, 66%; bp 70-72° (4 nun): cm -1 procedure B, ir (film) 3600-2400, 1711 (C = 0) From allyl acetate (la); ; NMR (CDC1 3) 62.5 (m, 4H, -CH 2 -), 5.85-6.25 (m, 3H, -CH=CH 2 ), 11.9 (s, lH, -C0 2 H). 3-Methyl-4-pentenoic Acid (2b). From crotyl acetate (lb); procedure B, 1.5 hr at 67°, 70%; bp 75-76° (4 nun): 2400, 1710 (C = 0), 1640, 1000, 920 cm -1 ir (film) 3600- ; NMR (CDCl3) ol.10 (d, 3H, J = 7 Hz, CH 3), 2.2-3.0 (m, 3H, -CH 2 -CH-), 4.85-6.15 (m, 3H, ~Cll=CH 2 ), 11.5 (s, lH, -C0 2 H). Anal. Calcd for C6 H10 0 2 : H, 8.87. C, 63.14; H, 8.83. Found: C, 63.06; 33 2,3-Dimethyl-4-pentenoic Acid (2c). From crotyl propanoate (le); procedure A, 1 hr at 25°, 75%; procedure B, 0.5 hr at 67°, 75%; bp 81-82° (3 nun): . ir (film) 3600-2400, 1710 (C = 0), 1644, 1000, -1 920 cm ; NMR (CDC1 3 ) ol.0-1.3 (overlapping d's, 6H, CH 3 ) , 2.1-2.7 (m, 2H, methines), 4.82-6.05 (m, 3H, -0-1=01 2 ) , 11.43 (s, lH, -C0 2 H). Anal. Calcd for C7 H12 0 2 : C, 65.60; H, 9.44. Pound: C, 65.43; H, 9. 28. 2,2,3-Trimethyl-4-pentenoic Acid (2d). From crotyl isobutyrate (ld); procedure A, 10 min at 25°, 80%; procedure B, 10 min at 25°, -.. 78%; bp 52° (0.07 nun): 1643, 1000, 923 cm - 1 ir (film) 3600-2400, 1705 (C = O), NMR (CDC1 3 ) ol.01 (d, 3H, J = 7 Hz, 01 3 ) , 1.13 and 1.15 (s, 3H, CH 3 ) , 2.52 (m, lH, methine), 4.85-6.l (m, 3H, -CH=CH 2 ) , 12.05 (s, lH, -C0 2 H). Anal. Calcd for C6 H14 0 2 : C, 67.57; H, 9.92. Found: C, 67.71; H, 10.12. (E[2-(l-Methyl-2-propenyl)-3-hexenoic Acid (2e). From crotyl (E}3-hexenoate (le); procedure A, 3 hr at 25°, 69%; evaporatively distilled at 90° (0.05 nun): ir (film) 3600-2400, 1710 (C = O), ~ 1645, 1000, 975, 920 cm -1 ; NMR (CDC1 3 ) o0.80-1.15 (m, 6H, CH 3 ) , 1.8-3.1 (m, 4H, allylic H's), 4.8-6.0 (m, SH, vinylic H's), 11.2 (s, lH, -C0 2 H). Anal. Calcd for C10 H1G0 2 : H, 9. 68. C, 71.39; H, 9.59. Found: C, 71.42; 34 2,4-Dimethyl-3-hexyl-4-pentenoic Acid (2f). From 2-methyl-2- nonenyl . propanoate (lf); procedure A, 20 hr at 25°, 71%; evaporatively ~ distilled at 100-120° (0.05 nun): 1650, 900 cm -1 ir (film) 3600-2400, 1710 (C = O), ; NMR (CDCl3) 60.8-1.5 (m, 16H), 1.54 and 1.65 (brs, 3H, vinylic CH 3), 2.1-3.5 (m, 2H, methines), 4.8, (m, 2H, vinylic H's), 11.20 (s, lH, -C0 2 H). Anal. Calcd for C13 H24 0 2 : C, 73.54; H, 11.39. Found: C, 73.67; H, 11.26. Removal of a-Silyl Impurities in Carboxylic Acids Prepared by Procedure B. A 2.0-g portion of the 4-pentenoic acid obtained by procedure B was esterified with excess diazomethane in ether solution and then refluxed with 5 wt% sodiLUIJ. methoxide in methanol for 2 hr. Water (20 ml) was added and the methanol was distilled over 1 hr. The reaction mixture was extracted with 20 ml of ether (extract discarded) and then acidified with cone hydrochloric acid. isolated by dichloromethane extraction. 29 The product acid was Distillation at 65° (4 mm) - afforded 1. 70 g of pure, colorless 4-pentenoic acid (la) (57% overall yield from allyl acetate). In exactly the same manner, pure 3-methyl-4-pentenoic acid (lb) was prepared in an overall yield of 50% from crotyl acetate. Detennination of Rearran~ement Half-lives. After addition of TMSCl or TBSCl to the reaction mixture to quench the enolate anion, a 300 µl aliquot was withdrawn and placed in an NMR tube. from o=l.5 to -1.0 was scanned. CH3 Si of the ketene acetal) 1~e region A peak at o~0.27 (assigned to the gradually disappeared and a new peak of 35 o:0.33 (assigned to the CH 3Si of the silyl ester) appeared at the same rate. When the two peaks reached the same height, the elapsed time was taken to be the half-life for the rearrangement. This method was used to follow the reaction with both trimethylsilyl and tert.butyldimethylsilyl derivatives. Lithium Diisopropylamide (LDA). Hexane-freeLDA was prepared by dropwise addition of 1 equiv of ~-butyl lithium in hexane to a stirred solution of 1.5 equiv of dry diisopropylamine in dry hexane (- 2M) at 0°. Following the addition, the viscous mixture was stirred for an additional 10 min, after which the hexane and excess amine were removed under reduced pressure at 0°. The flask was refilled with argon and the residual white solid was redissolved in sufficient dry TI-IF at o0 to give approximately an 0.3 M solution. When dissolu- tion was complete, the ice bath was replaced by a dry-ice/acetone (-78°) bath. (E}-4-Decenoic Acid (2g). A solution of 11.0 rmnol of LDA in 30 ml of dry 1HF was cooled to -78° and then 3.0 ml of dry HMPA was added. To this solution was added dropwise 1.70 g (10.0 rmnol) of 3-acetoxy-l-octene 3 3 C!i) and 1. 65 g (11. 0 rmnol) of TBSCl in 2 ml of dry THF over 5 min. The slightly yellow solution was stirred at -78° for an additional 2 min after which the cooling bath was removed, and the reaction mixture allowed to warm to 25° over 30 nun. The reaction mixture was stirred at 25° for an additional 2 hr and the product silyl ester was isolated by pentane extraction. 29 The crude, oily silyl ester was dissolved in 25 ml of THF, treated with 5 ml of 36 10% hydrochloric acid, and the mixture was stirred at 25° for 45 min to effect hydrolysis of the silyl ester. The reaction mixture was then poured into 30 ml of 5% aqueous soditml hydroxide solution and extracted with two 30-ml portions of ether (extracts discarded). After acidification with cone hydrochloric acid, the product acid was isolated by ether extraction. 29 Evaporative distillation of the residual oil (1.5 g) at 70° (0.003 nnn) afforded 1.41 g (83%) of - acid lg: NMR (CDC1 3 ) 61.13 (m, 6H, -CH 2 - ) , 1.98 (m, 2H, -Gl 2 ) , 2.20 (m, 4H, -CH 2 CH 2 C0 2 - ) , 5.25 (m, 2H, -CH=G1-), 11.0 (s, lH, -1 -C0 2 H); ir (CHC1 3 ) 3500-2400 (OH), 1710 (C = 0), 1285, 970 an . Anal. Calcd for C10 H16 0 2 : C, 70.55; H, 10.66. FoW1d: C, 70.51; H, 10.73. Comparison of the methyl ester with an authentic san1ple of methyl@4-decenoate3lt by VPC 26 (300 ft x 0.03 in open tubular colLUJID., TCEP, 110°, 20 ml/min, flame ionization) indicated that less than 0.5% of the ~-isomer was present. Q?[2-Methyl-2-(phenylthio)-4-decenoic Acid (2h). A solution of 20.S nunol of LDA in 75 ml of dry 11IF was cooled to -78°. To this rapidly stirred solution was added a mixture of 5.0 g (17.1 mmol) of ester lh in 5 ml of dry 1HF over a 10 min period. Following the """"" addition, the mixture was stirred at -78° for 5 min. After the addition of 7.5 ml of dry HMPA, 6.1 ml (20.5 mmol) of TBSCl in hexane was added and the cooling bath was removed after 2 min. The mixture was then allowed to warm to 25° and was stirred for 2 hr. The silyl ester was isolated by petroleum ether extraction 29 and amounted to 6.9 g of a yellow oil. This oil was stirred with a 37 solution of 15 ml of 5% hytlrochloriC acid an<l 75 ml of TI£F at 25° for 45 min to effect hydrolysis of the silyl ester. Petroletnn ether extraction 29 afforded 5.5 g of a yellow oil which was purified by chromatography on 150 g of acidic silica gel 28 with 20% ether/petroletnn ether. After elution with 250 ml of this solvent mixture, continued elution with 350 ml gave 4.4 g (88%) of the acid 2h. An """' analytical sample was prepared by evaporative distillation at 14D° (0 . 005 rrnn): NMR (CDCl3) 61.40 (s, 3H, QI 3 ) , 2.00 (m, 2H, allylic CH2), 2.48 (m, 2H, allylic CH2 ), 3.80 (m, 2H, vinylic H's), 7.37 (m, SH, phenyl), 10.5 (br s, UI, -C02 H); ir (CHC1 3 ) 3300-2400, 1740 (shoulder), 1695 (C = 0), 10.70, 975 cm Anal. Calcd for C11H21t02S: Found: -1 . C', 69.82; H, 8.27; S, 10.96. C, 69.86; H, 8. 22; S, 10.95. Methyl @)-2-(1-Hexyl-2-methoxy-2-propeny~-3-hexenoate (2i-Methyl Ester). A solution of 4 .10 rrnnol of LDA in 10 ml of <lry 'JlfF was cooled to -78°. To this rapidly stirred solution was added 1.0 g - (3. 73 rrnnol) of the ester li (a mixture of isomers) rn 1 ml of dry TifF over a 1.5 min period. After an additional 1 min, 2.64 ml (4 . 10 mmol) of TBSCl in HMPA was added, and the reaction mixture was stirrc<l for an additional 5 min. The cooling bath was then removed, and the reaction mixture was allowed to warm to 25° over 30 min. The mix - ture was then stirred at reflux (67°) for 2 hr and cooled to 25°. Pentane extraction afforded the silyl esters as an orange oil (1.5 g). This oil was dissolved in 8 ml of HMPA and was treated with 560 mg (5.6 mmol) of KHCQ3 and 527 mg (5.6 rrnnol) of KF·2H 20. The reaction mixture was stirred vigorously for 30 min, after which 1. 07 g (7.5 38 nnnol) of methyl iodide was added. Stirring was continued for 15 hr after which the methyl esters were isolated by pentane extraction. 29 The residual orange oil (1.0 g) was purified by medium-pressure chromatography 28 on 2.5 x SO cm of silica gel with 4% ether/petroleumether at a flow rate of 2 ml/min. After elution with 300 ml, con- tinued elution with 20 ml of the same solvent system gave 361 mg (34%) of the more mobile isomer as a colorless oil. An analytical smnple was prepared by evaporative distillation at 70-80° (0.005 rrun): Rf= 0.49 (silica gel, 10% ether/petroleum ether); NMR (CDC1 3) 63.45 (s, 3H, ether CH3), 3.68 (s, 311, ester CH3), 3.87 (m, 211, Oh=C-0-), 5.40 (m, 2H, -CH=CH-); ir (CHC1 3 ) 1752 (C = 0), 1660, 1615, 1165, 1070, 970 cm -1 Anal. Calcd for C17H3003: C, 72.30; H, 10.71. Found: C, 72.25; H, 10.74. Continued elution with 30 ml gave 225 mg (21%) of a mixture of the two isomers. Finally elution with an additional 60 ml gave 220 mg (21%) of the less mobile isomer. An analytical sample was by evaporative distillation (70-80° /0.005 nun): prepared Rf= 0.33 (silica gel, 10% ether/petroleum ether); NMR (CDCb) 63.47 (s, 3H, ether Cl-1 3 ) , 3.60 (s, 3H, ester CH3), 3.88 (br ~ 2H, CH2= C-0), 5.45 (m, 2H, -CH=Cll-); ir (CHCl3) 1752 (C = 0), 1660, 1615, 1165, 1070, 975 cm Anal. Calcd for C11H3003: H, 10. 66. C, 72.30; H, 10.71. - l Found: C~ 72.34; 39 2-Butyl-3-methyl-4-pentenoic Acid (2k). To a stirred suspension of 520 mg (8.0 rrnnol) of zinc dust and 720 mg (4.80 nmol) of TBSCl in 30 ml of dry 1HF and 6 ml of dry HMPA, was added 1.0 g (4.01 rmnol) of - the a-bromo ester lk over a 10-min period. Following the addition, the reaction mixture was stirred at reflux for 1.5 hr, cooled to room temperature, and then diluted with 300 ml of pentane containing 2 ml of pyridine. The pentane solution was filtered and then washed with three 30-ml portions of ice water, dried (Mgso .. ), aml evaporated at reduced pressure. The resulting oil (1.2 g) was stirred with 5 ml of 10% hydrochloric acid in 25 ml of TIIF for 45 min to effect hydrolysis of the silyl ester. The mixture was diluted with 20 ml of 5% aqueous sodilllll hydroxide solution and washed with two 50-ml portions of ether (washings discarded). This solution was acidified with cone hydro- chloric acid and the product acid was isolated by ether extraction. 29 This afforded 499 mg (73%) of a colorless oil which was homogeneous by TLC (silica gel, 50% ether/petroleum ether). An analytical was prepared by evaporative distillation at 60° (0.05 mm): sample NMR (CDC1 3 ) ol.07 (cl, 2H, J = 6 Hz, Clh), 2.30 (m, 21-1, mcthincs), 4.8-6.0 (m, 3H, -Qf=CH2), 10.4 (brs, HI, C0 2H); i r (Cl!Cl 3 ) 3400-2400, 1705 (C = 0), 1645, 1415, 990, 920 cm Anal. Calcd for C10H1a02: - l . C, 70.55; H, 10.66. Found: C, 70.49; H, 10.69. Stereochemistry of the Rearrangement. Enolization and Claisen rearrangement was studied under four sets of conditions (TABLES III and IV). 40 A. Enolization in TI-IF; Rearrangement as the Silyl Ketene Acetal. A solution of 1.1 equiv of LDA in dry TI-IF (0.3 M) was cooled to -78°. To this rapidly stirred solution was added 1.0 equiv of the ester, dropwise over 4 min. Following the addition, the reaction mixture was stirred for 2.5 min and then quenched with 1.1 equiv of TBSCl in HMPA. After an additional 2 min at -78°, the reaction mixture was allowed to warm to 25° during 20 min and was then stirred at reflux (67°) for 1-2 hr. B. Enolization in 23% HMPA-TI-IF; Rearran~ement as the Silyl Ketene Acetal. To a stirred solution of 1.1 equiv of LDA in dry 1HF at -78° was added sufficient dry HMPA to adjust the solvent composition to 23 vol% HMPA-11-IF. This slightly yellow, non-homogeneous solution was treated with the dropwise addition of 1.0 equiv of the ester over 4 min. After an additional 2.5 min at -78°, 1.1 equiv of TBSCl in hexane was added. The reaction mixture was stirred for an additional 2 min at -78°, allowed to warm to 25° over 20 min and then stirred at reflux (67°) for 1-2 hr. C. Enolization in TI-IF; Rearrangement as the Enolate Anion. enolization was carried out as described in A above. however, no TBSCl was added. The In this case, The reaction mixture was allowed to warm to 25° over 20 min and was then stirred at 25° for 1 hr. D. Anion. Enolization in 23% HMPA-1HF; Rearrangement as the Enolate Enolization was carried out as described in B above. case, however, no TBSCl was added. ~ In this The reaction mixture was allowed to warm to 25° over 20 min and was then stirred at 25° for 1 hr. 41 Rearrangement of@- and @-2-Butenyl Propanoate (12 and 13). After rearrangement as described above (5.0 rrunol), the reaction mixtures obtained in C and D were diluted with 30 ml of 5% aqueous ol\ "" sodium hydroxide solution, and this solution was extracte<l with two 30-ml portions of ether (extracts discarded). The basic solution was then acidified with cone hydrochloric acid and ice. 'The cold, ac i<l ic aqueous phase was extracted with four 20-ml portions of ether. The combined ethereal extracts were washed with 20-ml portions of water and saturated brine and dried (MgS0 4 ). The solvents were then distilled through a 30-cm, vacuum~jacketed, Vigreux collUTlil and evaporative distillation of the residue at 90° (2 rrnn) afforded a mixture of the erythro 1i_ and threo !,i acids. For the reactions in A and B, after 1 hr at 67° the silyl esters .,A. -"" were isolated by pentane extraction. 29 The residue was dissolved in 15 ml of TIIF and treated with 3 ml of 10% hydrochloric acid. This mixture was stirred for 45 min at 25° and then worked up as <lescribed for C and D above. """ """ acids 14 and 15. Evaporative distillation affor<led a mixture of the Treatment of 64-mg (0.5 rrunol) portions of each of the aci<l mixtures with S ml of ether containing 1.5 rrunol of diazomethane 35 served to convert the acids to the corresponding methyl esters. These mixtures were analyzed by VPC 2 8 (90°, 1/8 in x 27 ft l 5% Carbowax 20 M, 20 ml/min, flame ionization). - The erythro-ester 14 had a retention - time of 54 min; the threo-ester 15, 58 min. volatile compoW1ds in the mixtures. analysis is recorded in TABLE III. There were no other The data obtaine:d from this 42 Rearrangement of(!?)- and ©-2-Methoxy-2-nonenyl Pentanoate (lj-§_ -- and lj-_D. Esters lj-E and lj-Z were rearranged only as described .-.. in A and B above (1.95 mmol). 1be silyl esters were isolated as .,.. "" described for the rearrangement of (E)- and (6t-2-butenyl propanoate - (12 and 13). ......... 1be crude mixture of silyl esters was then stirred with 490 mg (4.90 mmol) KHC03 and 367 mg (3.90 mmol) of KF•2H 20 in 5 ml of HMPA for 18 hr to effect cleavage of the silyl esters. Following this , 364 µl (831 mg, 5.85 nnnol) of methyl iodide was added and the mixture was stirred for an additional 1. 5 hr at room temperature. 1be methyl esters were then isolated by pentane extraction29 including a base wash. The ratio of the two isomers in this mixture could be deter- mined from peak heights of the ester methyl signals in the "NrvIR spectra . 1be two isomers were cleanly separated by mediwn-pressure chromatography28 on 1.25 x 50 cm of silica gel with 5% ether/petrolewn ether at a flow rate of 1 ml/min. Analytical samples were prepared by evaporative distillation at 60° (0.08 mm). The more mobile isomer was tentatively assigned the erythro-configuration 16 (see discussion): ~ Rf= 0. 50 (silica gel, 10% ether/petrolewn ether) . NMR (CDC1 3 ) 83.51 (s, 3H, ether CH3); 3. 70 (s, 3H, ester CH3), 3. 95 (m, 2H, CH =C); ir (CHCl3) 1725 (C = 0), 1660 and 1610 (C = C), 1190, 1160, 1115, 1060 cm _1 Anal. Calcd for C1GH3o03: C, 71 . 07; H, 11.18. Found: C, 71 . 11 ; H, 11.25. 1be less mobile isomer was assigned the threo-configuration 17 """"- (see discussion): Rf= 0.35 (silica gel, 10% ether/petrolewn ether); NMR (CDCb) 03.49 (s, 3H, ether CH 3), 3.63 (s, 3H, ester CH 3), 3.88 (m, 2H, CH 2=C); ir (CHC1 3 ) 1730 (C = 0), 1655 and 1615 (C = C), 43 1285, 1190, 1160, 1120, 1065 cm Anal. Calcd for C16 H30 0 3 : C, 71 . 07; H, 11.18. Found: C, 70.98; H, 11.25. The data obtained from these rearrangements is recorded in TABLE IV. Ozonization of Erythro-Acid 14. A solution of 754 mg (5.9 nunol) - of the acid mixture containing 90% erythro-acid 14 (VPC analysis of methyl esters, see above) in 25 ml of ethyl acetate and 25 ml of acetic acid was cooled to -10°. Ozone 36 was passed through the solution until no more ozone was absorbed. The reaction mixture was then purged with argon to remove dissolved ozone and was treated with 10 ml of 15% aqueous hydrogen peroxide solution. for 16 hr. This solution was stirred at 25° The solvents were then removed at reduced pressure and the residue was dissolved in 50 ml of 3% aqueous sodium hydroxide solution. This basic solution was extracted with three 30-ml portions of ether (extracts discarded) and acidified with 40 ml of 2N aqueous sulfuric acid. This acidic solution was continuously extracted with ether for 16 hr, after which evaporation of the ether· extract afforded 830 mg of a white solid. One recrystallization of this material from 20 ml of water gave 543 mg of meso-2,3-dimethylsuccinic acid (70% based on amount of erythro-acid ......... 14 initially present: mp 202-204° dee (Lit 37 209°). Ozonization of Threo-Acid 15. As described above for the erythro- acid 14, 606 mg (4.73 nnnol) of a mixture containing 90% of the threo- """" - acid 15 was treated with ozone and then aqueous hydrogen peroxide. 44 After continuous extraction, 648 mg of a white solid was obtained. One recrystallization from water gave 453 mg (73% based on the amount - of threo-acid 15 initially present) of d,l-2,3-dimethylsuccinic acid: mp 118-121° (Lit 37 129°). Preearation of Silyl Ketene Acetals of Simple Esters (TABLE V) . • A. Enolization in TifF. A solution of 5.5 mmol of LDA in 15 ml of dry THF was cooled to -78°. To this rapidly stirred solution was added 5.0 mmol of the ester 18 over 4 min. Following the addition, the reaction mixture was stirred at -78° for 2.5 min and then treated with 3.59 ml (5.5 mmol) of TBSCl in HMPA. After an additional 2 min at -78°, the reaction mixture was allowed to warm to 25° over 30 min . Pentane extraction 29 then afforded a quantitative yield of a mixture - - of the ketene acetals 19 and 20. B. Enolization in 23 vol% HMPA-1HF. A solution of 5.5 mmol of LDA in 15 ml of dry TifF was cooled to -78° and 4.5 ml of HMPA was added. To this rapidly stirred solution was added 5.0 rrunol of the - ester 18, dropwise over 4 min. After an additional 2.5 min at -78°, 1.59 ml (5.5 mmol) of TBSCl in hexane was added. This mixture was stirred for 2 min at -78° and then allowed to warm to 25° over 30 min. Pentane extraction 29 afforded a quantitative yield of a mixture of - ketene acetals 19 and 20. ~ These mixtures of ketene acetals obtained in A and B were subjected to NMR analysis. Only signals which could be assigned to -- the two possible isomeric ketene acetals 19 and 20 were present """'" (TABLE VI). The ratios of the isomers were determined by integration 45 and are recorded in TABLE V. C. Enolization of Methrl ButL:Eate (18al in the Presence of Var:iin& Amounts of HMPA (TABLE VII~ . Methyl butyrate (18a) ........._ was enol- ized as described in B in dry THF containing varied concentrations of HMPA. """ When 2 equiv or less of HMPA was present (entries 1-5), the enolates were quenched with TBSCl in HMPA. When more than 2 cqujv of HMPA was present, the enolates were quenched with TBSCl in hexane (entry 6). A variety of other experiments were performed with methyl butyrate 18a. ,,....._ These are described in Footnotes to TABLE VII. The -- resulting mixtures of silyl ketene acetals 19a and 20a were analyzed ..-... by NMR as described above. Pre2aration of the Silll Enol Ethers of 3-Pentanone. The tert.- butyldirnethylsilyl enol ethers of 3-pentanone were prepared by - enolization as described for the esters 18 in A and B above. The isomer ratios were detennined by NMR analysis and by VPC 28 analysis (110 , 8 ft x \1 in 4% SE-30, 60 ml/min, thermocouple, not corrected for sensitivities). The data obtained is recorded in TABLE V. These isomers were preparatively separated under the same conditions. TI1e . d by NMR2 i structures were read i· 1y ass1gne 22 analysis. @}-3-(~.-Butyldirnethylsilyloxy)-2-pentene. Retention time= 7.5 min; NMR (COC1 3 ) o0.13 (s, 6H, CH 3 Si), 0.95 (s, 9H, (CHJ 3 CSi), 1.03 (t, 3H, J = 7 Hz, CH 3 ) , 1.55 (d, 3H, J = 7 Hz, vinylic CI-1 3 ) , 2.10 (q, 2H, J = 7 Hz, <l Hz homoallylic coupling, -01 2 - ) , 4.60 (q, lH, J = 7 Hz, vinylic H). 46 (Z)-3-(~. -Butyldimethylsilyloxy)-2-pentene. Retention time 8.5 min; NMR (CDC1 3 ) cS0.13 (s, 6H, CH 3 Si), 0.99 (s, 9H, (CH3) 3CSi), 1.05 (t, 3H, J = 7 Hz, CH 3), 1.56 . (d oft, 3H, J = 6.S and 1.5 llz, vinylic CH 3 ) , 2.06 (q, 2H, J = 7 Hz, broadened by allylic and homo allylic coupling >l Hz, -0-12 - ) , 4.54 (q oft, lH, J = 7 and 1 Hz, vinylic H). 47 References and Notes ft (1) • .... (a) Grateful acknowledgement is made for support of this work by the National Science Foundation and the National Institutes of Health. (b) National Science Foundation Predoctoral Fellow, 1972-75. (2) A. W. Burgstahler and I. C. Nordin, J. Amer. Chem. Soc., 83, 198 (1961); G. Saucy and R. l\1arbet, Helv . .Cfilln. Acta, SO, 209l(l967); K. Sakai, J. I de, 0. Oda, and N. Nakamura, TetrahedTon Lett. , 1287 (1972). (3) W. S. Johnson, L. Werthermann, W. R. Bartlett, T. J. Brockson, T.-t. Li, D. J. Faulkner, and M. R. Petersen, J. Amer. Chem. Soc., 92, 741 (1970). (4) A. E. Wick, D. Felix, K. Steen, and A. Escherunoser, Helv. Chim. Acta, 47 , 2425 (1964). (5) R. T. Arnold and C. Hoffman, Syn . Conun., l, 27 (1972), and earlier work; S. Julia, M. Julia, and G. Linstrumelle, Bull. Soc. Chim. Fr., 2693 (1964). (6) M. (7) R. E. Ireland and IL II. Mueller, J. Amer. Chem. Soc., 94, 5897 - - - W. Rathke and A. Lindert, J. Amer. Chem. Soc., ~l3, 2318 (1971) . (1972). (8) - M. W. Rathke and D. F. Sullivan, Syn. Conunun., 3, 67 (1973). A. (9) Rearrangement of zinc enolate anions of allyl esters has been observed but is plagued with difficulties: J. E. Baldw:in and J. A. Walker, Chem. Conunun., 117 (1973). (10) See Part II of this thesis. (11) W. Grell and H. Machleidt, Ann. Chem., ....699, 53 (1966). (12) G. B. Gill, Quart. Rev. (London), 22, 338 (1968). (13) H. Takahashi, K. Oshima, H. Yamamoto, and H. Nozaki, J. Amer. Chem. Soc., 95, 5803 (1973). · (14) W. von E. Doering and W. R. Roth, Tetrahedron, 18, 67 (1962). (15) P. Vittorelli, T. Winkler, H.-J. Hansen, and II. Schmid, llelv. Chim. Acta, .51, 1457 (1968) (16) W. Sucrow and W. Richter, Chern. Ber., 104, 3679 (1971). - - ~ -- 48 (17) D. J . Faulkner and M. R. Petersen, Tetrahedron Lett., 3243 (1 969) . (18) J. A. Katzenellenbogen and K. J. Christy, J. Org. Chem., 39, 3315 (1974). .-. (19) E. J. Corey and A. Venkateswarlu, J. Amer. Chem. Soc., 94, 6190 (1972). .-. (20) J . Shaw, D. Kunerth, J. Sherry, Tetrahedron Lett., 689 (1973) . (21) For assignments of correspon<l ing enol acetates see , 11. 0 . I louse and V. Kramar, J. Org. Chem., 28, 3362 (1963). (22) For allylic coupling Jcis >.Jr rans, usually; for homoally1 ic coupling J trans >Jc is, consistently: L. M. J:Kkman and S. Sternhell, "Applications of Nuclear Magncti.c Resonance Spectroscopy in Organic Chemistry", second e<lition, Pergamon Press, New York, 1969, pp 316-326. (23) C. B. Chapleo, P. Hallett, B. Lythgoe, and P. W. Wright, Tetrahedron Lett., 847 (1974). (24) H. 0. House, D. S. Crumrine, A. Y. Teranishi, and H. D. Olmstead , J. Amer. Chem. Soc., 95, 3310 (1973). (25) E. A. Jeffery, A. Meisters, and T. Mole, J. Organomet. Chem . , 74, 373 (1974). .-.... (26) J.E . Dubois and P. Fellmarm, Tetrahedron Lett., 122 5, (1975). (27) A. I . Meyers, G. Knaus, and K. Karnata, J. Amer. Chem. Soc. , % , 268 (1974) ; A. I. Meyers and G. Knaus, .J. Airier. Chem. Soc . , ~' 6508 (1974). ,,.,... (28) Boiling points are uncorrected. Infrared (ir) spectra were determined on a Perkin-Elmer 237B grating infrared spectr omet er and nuclear magnetic resonance (NMR) spectra were recorded using a Varian T-60 spectrometer. Chemical shifts are reported as 6 values in parts per million relative to TMS (6 TMS = 0.0 ppm) as an internal standard. Deuteriochloroform for NMR and chlorofonn for ir spectra were filtered through neutral alumi na befo re use. - """ Vapor phase chromatographic (VPC) analyses were determined on either a Hewlett-Packard 5750 equipped with a flame i onization detector or a Varian 920 equipped with a thermal con<luctivity detector using helium as the carrier gas under the inJicatcd conditions. The indicated liquid phase was absorbed on 60-80 mesh Chrornosorb WAW DMCS . 49 Silica gel coltmll1s used the 0.05-0.2 rrrn silica gel manufactured by E. Merck &Co., Dannstadt, Germany. Acidic silica gel refers to Silicar CC-4 Special "For ColWTU1 Chromatography", sold by Mallinckrodt Chemical Works, St. Louis, Missouri. Preparative medium-pressure chromatography was pcrfonne<l using glass colunms of the indicated length and diameter with fittings supplied by Laboratory Data Control, Riviera Beach, Fla., and an instrument minipt.nnp supplied by Milton Roy Co., St. Petersburg, Horicla (instrumentation designed by R. H. Mueller, these laboratories, and copies are available on request). The columns were packed with silica gel H "for TLC acc. to Stahl" (10-40 µ) manufactured by E. Merck &Co., Dannstadt, Germany. Solvents were degassed under water aspirator vacuum prior to use. Analytical thin layer chromatography was conducted on 2.5 x 10 cm Pre-coated TLC Plates, Silica Gel 60 F-254, layer thickness 0.25 rrnn manufactured by E. Merck &Co., Darmstadt, Germany. "Dry" solvents were dried irrrnediately prior to use. Ether and tetrahydrofuran (1HF) were distilled from lithium aluminum hydride; pyridine, triethylamine, diisopropylamine, N-isopropylcyclohexylamine, trimethychlorosilane (TMSCl), hexamethylphosphoramide (HMPA), and benzene were distilled from calcium hydride; dichloromethane, methyl io<li<le, and hexane were distilled from phosphorous pentoxide. "PetroleLUn ether" refers to the "Analyzed Reagent" grade hydrocarbon fraction, bp .30-60°, which is supplied by J. T. Baker Co., Phillipsburg, N. J., and was not further purified. Standard solutions of tert.-butyldirnethylchlorosilane (TBSCl) in hexane (ca. 3.3 M) or HMPA (ca. 1.5 M) were employed. Reactions were run under an argon atmosphere arranged with a mercury bubbler so that the system could be alternately evacuated and filled with argon and left under a positive pressure. Microanalyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan. (29) In cases where the products were isolated "by solvent extraction", the procedure generally followed was to dilute the reaction mixture with the indicateJ solvent or to extract the aqueous solution with several portions of the indicated solvent; then the combined organic layers were washed with several portions of water followed by saturated brine. The organic layer was dried over anhydrous sodium or magnesium sulfate, then filtered, and the solvent was evaporated from the filtrate under reduced pressure (water aspirator) using a rotary evaporator. The use of the tenns "base wash" or "acid wash" indicate washjng the organic solution with saturate<l aqueous sodium bicarbonate so solution or with dilute aqueous hydrochloric acid, respectively, prior to the aforementioned wash with water. (30) L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, 1967, p 584. (31) E. J. Corey and H. Yamamoto, J. Amer. Chern. Soc., 92, 226 (1970). (32) For preparation of 2-bromohexanoyl chloride: D. N. llarpp, Q. Bao, C. Coyle, J. G. Gleason, S. Horovitch, Org. Synthesis, ~ (1975) in press; for 2-(phenylthio)-propanoyl chlorjde: V. Rosnati, F. Sannicolo, an<l G. Zecchi, Gazz. Chim. Ital., 100, 591 (1970). ~ L. (33) M. S. Kharasch, G. Sosnovsky, and N. C. Yang, J. Amer. Chem. Soc., - 81, 5819 (1959). (34) (35) H. Sprecher, Lipids, 3, 14 (1968). "' F. Arndt, Org. Synthesis, Coll. Vol. Ao 2, 165 (1943). (36) L. I. Smith, F. L. Greenwood, and 0. Hudrlik, Org. Synthesis, Coll. Vol. 3, 673 (1955). (37) A. Higson and J. F. Thorpe, J. Chem. S~ 89, 1463 (1906); E. Berner and R. Leonardsen, Ann. Chem., ~ 1, 23, ~O (J 939). - 51 PART II Construction of the Prostanoid Skeleton 1 52 No family of molecules since the steroids has attracted the interest and effort of synthetic chemists as strongly as have the prostaglandins. Recent efforts have involved the search for flexible synthetic schemes which will allow preparation of a variety of analogs. We report here a synthetic approach which incorporates connection of a "top-half'' and a "bottom-half" of the prostanoid skeleton in a key carbon-carbon bond forming reaction. 0 0 0 OH OH 1 .- H 0 0 OH OH 3 .,._ 2 .- 0 ·""'~ OH N' = OH 4 53 An intriguing possibility for this approach was formation of the carbon-carbon bond with an aliphatic Claisen rearrangement. This reaction (5 -+ 6) would not only provide an efficient means for fonnation .,,... """ of the desired bond but also would result in the proper number of suitably functionalized carbon atoms for subsequent fonnation of the cyclopentanone ring system. z ~R z ¢x=R' 1 x Y'R2 R2 y y 5 6 """ The requirements that only one equivalent of each half of the molecule be employed in construction of the precursor ........ 5 and that conditions of the reaction be compatible with a variety of functional groups prompted development of the ester enolatc Claisen rearrangement. 2 ' 3 To demonstrate the viability of this approach, synthesis of - dihydrojasmone (15), a virtual touchstone of cyclopentenone syntheses, was undertaken. The successful route is described in SCHEME I. 2 - Phosphonates such as 7b, introduced by Grell and Machlcidt," ;:ire a useful source of functionalized allylic alcohols such as ....... 10. - When the ester 11 was subjected to enolization with lithiwn isopropyl cyclohexylamide (LICA) and the cnolate was trapped with trimcthyl- 54 Synthesis of Dihydrojasrnone (15). 8 SQ-IEME I. + 7b .,.,.. HI~ 0 b 100% 8 ~ OH 10 .,.,.,, d-f OC2Hs c 85% ~ ~ 0 11 _... g 73% from 11 ~~ 13 12 h,i 85% a, NaH, THF; b, LiAlH j 93% H3 14 a 0 -15 , ether; c , propanoic anhydride, pyridine; d, LI CA, THF, - 78° ; e, TMSCl; f, 65°, 7 hr; g, CH3S03H, EtOH; h, DIBAH, t oluene, - 78°; i, NaOH, a q CH 30H, 25 ° ; j, KOH, aq CH 30H, reflux. 55 chlorosilane (TMSCl), rearrangement 3 occurred without incident to give - silyl ester 12. The enol ether fllllctionality not only serves as an ultimate source of a methyl ketone for aldol condensation but also is a convenient handle for reduction of the silyl ester carbon to the aldehyde oxidation state. This reduction is accomplished by conver- - sion of the silyl ester 12 to the lactone 13 with a trace of acid in """" ethanol followed by reaction with diisobutylaluminum hydride (DIBAH). 5 Finally, aldol condensation 6 and double bond migration 7 complete this - synthesis of dihydrojasmone (15). 8 This same approach was then used for the construction of the prostaglandin skeleton, with initial efforts focused on preparation - - and transformations of esters 16 - 18. 0 0 - 16 17 - X = c::N X = CONH2 18 - Use of readily avaiiable 7-cyanoheptanal (19) 9 as a substrate in the Wittig reaction produced equivalent amounts of the geometrical isomers of ester - 20 (SCHEME II). The methoxy series was adopted rn later stages of these studies because it offered the advantage of simpler interpretation of NMR spectra of intermediates in the synthesis. Selective reduction of the cyano esters ......._ 20 with lithium bo- r ohydride 10 in tetrahydrofuran (THF) provided the desired alcohols 21. '°"""'"" 24 aa, NaH, THF; b, LiBH1., THF; C, H202, NaOH, aq C2H5 0H; d, Et 3 N, 25°; e, LICA, THF, -78°; f, TMSCl; g, 67°, 3.5 hr; h, CH 3 S0 3 H, C2 H5 0H. 57 An alternate masked carboxylic acid fW1ction, the primary amiJe 22, was available by hydration of the nitrile in the presence of the enol ether with basic hydrogen peroxide. Reaction of the alcohol 21 - or 22 with the Q_-nitrophenyl ester 11 of the acid in triethylarnine was the most satisfactory procedure for preparation of es t ers of these y,o-W1saturated acids. With the esters 16 and 17 in hand, their further conversion to cyclopentenone derivatives was investigated. Eriolization, silylation and Claisen rearrangement of cyano ester 16 resulted in a mixture of ~ products containing C-silylate<l nitrile. The siJylation of aljphatic nitriles has now been studied and fonnation of C-silylate<l pro<lucts, even with one equivalent of base and trialkylchlorosilane, has been demonstrated. 1 2 Because of this problem, use of the nitrile as a masked carboxylic acid was abandoned in favor of the primary amide. - Rearrangement of amide-ester 17 proceeded in good yield to provide a intermediate silyl ester which was directly transfonned to the l actone - 24 with a trace of methanesulfonic acid in ethanol. - Attempted reduction of amide-lactone 24 with one equiva l ent of diisobutylaluminum hydride 5 resulted in complete recovery of the starting lactone; apparently the reagent is consume<l hy r eaction with the acidic amide proton. The r e<luction was accomplished wj t h two equivalents of hydride reagent, but treatment of the r eduction product with aqueous base to cause aldol condensation 6 pentenone nor f)-ketol. produced nei the r cyclo- A possible reason for th is is that the :JC id i ty of the B,y-W1saturated aldehyde was resulting in extensive conjug~1tion of the double bond. 58 If this were fodeed the case, isolation of the double bond was a possible solution. 18 This suggested preparation of ester Moving the double bond to a position where it (SCHEME II I) . would not interfere with the aldol condensation also simplified ester - formation; now, the acid chloride 25 served well for preparation of the ester. - Rearrangement of ester 18, using lithium disopropyl- amide (LDA) and tert.-butyldimethylchlorosilane (TBSCU,3 , 13 led to - the silyl ester 26 which, as above, could be converted with acid into - the lactone 27. Reduction with two equivalents of DIBAll 5 and ;:ildol condensation 6 with aqueous methanolic sodium hydroxide provided the - cyclopentenone 28. - This verified that the trouble with these react i ons on lactone 24 was the position of the double bond. - -- As the lactone 27 or the cyclopentenone 28, the molecul e could not be subjected to reaction conditions sufficiently vigorous to effect hydrolysis of the primary amide. intermediate stage. This hydrolysis was attempted at the - Lactone 27 was reduced as before and the reduc - - tion product was protected as the acetal 31. Saponification of the primary amide, acidic hydrolysis of the acetals and finally, a1dol condensation in aqueous alcoholic base gave the cyclopentenone-aci<l 30 in low yield. ~ An alternate point in the synthetic scheme where saponif ication was possible was immediately after Cl a i sen rearrange ment. Basic hydrolysis of the silyl ester --. 26, followed by neutr;:il - - ization gave the lactone-acid 29 in good yield. Reduction , aga in with two equivalents of DIBAH, 6 and aldol condensation using pipcridinium acetate 14 in refluxing benzene provided the cyclopentenone-acid - 30 in more satisfactory overall yield. 59 SQ-lEME III. Synthesis of Prostanoic Acid Derivatives 28 and 30.a - 22a a + OTB • 2 b h H 65% - ~ from 18 OTBS - from 18 29 f ,j 0 2 0 :\''~H h,j, g 0 -~86% from 27 "'V" 0 :\.''~NH2 28 aa, Et 3 N, CH 2Cl 2 , 25°; b, LDA, THF, -78°; c, TBSCl; d, 67°, 3 hr; e, CH3S03H, CH30H; f, DIBAH, Et20, -78°; g, aq NaOH, CH30H, 25°; h, aq NaOH, CH 30H, reflux 16 hr, then neutralize, i, HOAc, piperidine, C6H6; j, aq HCl. bTBS = tert.-butyldimethylsilyl. 60 Having demonstrated that the prostaglandin skeleton could be constructed in this manner, we refocused attention on the problematic double bond in the lower side chain. An alternate solution would be to block apparent conjugation of the double bond during the a ldol conden sation; a methyl group should serve this purpose well. The 12-methyl was also attractive because it should block in vivo deactivation of the PGA via migration of the enone double bond to produce the less active PGB structure. Our synthetic approach to 12-methyl PG/\ 1 (32) would also give us the opportunity to investigate a sequence in which generation of the allylic alcohol functionality in the lower side chain is coupled to enolate formation necessary for the Claisen rearrangement. Two - electron reduction of a,8-unsaturated-y,o-epoxy es ters such as 33 - should give the enolate 34. - acetal 35. Silylation would provide the silyl ketene If the alcohol portion of this molecule were an allylic alcohol, this process could be followed by Claisen rearrangement. ~\\~OH - OH - (ctt,l 2 ctto l~ 2e 0 32 (CH3) 2CHO~ - 0 33 (CH,)2CHO~ OSiR 3 35 OSiR3 34 ....... 0 61 - Epoxy esters such as 33 are readily available by peracid oxidation 15 of the corresponding dienoic esters. Several reduction methods were examined and are outlined in TABLE I. Initial efforts were directed toward finding a system in which both reduction an<l silylation were possible in the same reaction mixture so that the reduction and Claisen rearrangement could be performed in a single step. A promising system for this transfor- mation was sodiuriJ. in 1HF-hexamethylphosphoramide (HMPA). 16 ' 17 During initial attempts, reductions employing these conditions produced a myriad of products but little or none of the desired reduction product. Only under very specific conditions, two to three equivalents of the Na-HMPA-TIIF solution added in one portion to a rapidly stirred - solution of ester 33 in HMPA-'TIIF at -78° followed by addition of TBSCl, could even low yields of the reduction products be obtained. - The intermediate silyl ketene acetal 35, which is formed W1der these -- - conditions, is readily hydrolyzed to the siloxy esters 36b and 37b for analysis. Quenching the reaction mixture with solid ammonium chloride - - gave nearly identical yield of the alcohols 36a and 37a and demonstrated that the problems were arising during reduction, not silylation. A second distinct disadvantage of this method of reduction was - that it produced the trans-isomer 36b and the cis-isomer 37b in nearly ..._ equal proportions (VPC analysis). Reduction with a mixture of zinc and TBSCl in HMPA-THF had proven useful in the preparation of silyl ketene acetals from a-bromo - esters, 3 but this method failed to reduce the epoxy ester 33. - - Finally a high yield of 2lcohols 36a and 37a was realized by reduction with 62 TABLE I. Reduction of Epoxy Ester 33. (CH 3 ) 2 CH~ reagents . " • (CH3) 2 CHO!,~ -(CH1)2CHl~ + 33 36 0 a series, R = H; b series, R = TBS Yiel<l( %)a Entry Reagents R 1 1) 2 equiv Na, llf\.1PA, TBS 37 H 42 OR OR 37 .- -- 36/37b 60/40 TIIF, - 78° 2) TBSCl 3) HOAc, H20 2 1) 3 equiv Na, Tiff -78° HMPA, ' 2) NI-It.Cl 3 1) Zn, TBSCl, llMPA, Tiff, 67° 4 1) 3 equiv Li, NH3, THF, -78° 2) NH1;Cl aAfter isolation and chromatography. {) H 79 bBy VPC Analysis. 89/11 lithiurn in anunonia-TIIF. 63 The best results were obtained when the reduction was perfonned with 3 equivalents of lithium at -78° for 1 min, and then the reaction mixture was quenched with solid anunonium chloride. -- - In this case an 89:11 ratio of 36a and 37a was obtained (VPC analysis). These isomers were easily separated by silica gel chromatography after convcrsion 18 to the corresponding silyl ethers 36b and 37b. tAAN .-- The stereochemical assignment for these two isomers rests on infrared spectral data. 19 The major isomer exhibits a medium band at 970 cm- 1 , indicative of a trans-disubstituted ethylene. No such band is present in the ir spectrum of the minor isomer. Since the one step process was effectively ruled out by the necessity of perfonning the reduction in annnonia, enolization of the reduction products had to be exan1ined. - Enolization of both the hydroxy - - esters 36a and 37a and the siloxy esters 36b and 37b with LDA followc<l ~ by trapping with TBSCl gave the silyl ketene acetal 35. Competing elimination was not a problem. -- Efforts then turned to synthesis of the epoxy ester 50 or its reduced derivative ..._ 51. The acid fragment for these esters was prepared as described in SCHEME IV. - The a-(phenylthio) ester 40 was readily available via Claisen rearrangement of allylic ester AA. 38 3 followed by esterification. Desulfenylation 20 by mild heating of the sulfoxides obtained by oxidation with MCPBA produced a mixture of unsaturatec.1 - esters 41 and 42 in the ratio 78:22. The mixture of diasteriomeric .-. sulfoxides obtained in the oxidation was separated by silica gel chromatography, and the sulfoxides were independently pyrolized. The more mobile isomer gave the olcfins in a 68:32 ratio 64 Preparation of the Acid Fragment for Ester 50. 8 SCl-IEME IV. ~ ref. 88% cn(f\f C5HsS ' r•HsS CH 38 """'" OR % CH3 + d,99% (39 R=H a 91% ~ R = CH3 - CH3 42 ~ CH3 CH3 t43R = H e 86% 44 ._, R = .E_-N02 C5H4 0 ff 71% br9% .E_-N02C 6 H4 0 ,.. 45 H r 0 H + 0 OH 48 ~ a 0 OH 49 ~ a, NaH, CH3l, THF; b, MCPBA, CHCl3; c, 60°, 2 hr; d, KOH, CH30H; e, .E_-nitrophenyl trifluoroacetate, Et3N; f, 3 equiv Li, NH 3 , THF, -78°; g, LiOH, aq CH30H. 65 (41:42) and the less mobile isomer, in a 90:10 ratio . .No JtA- - This synthesis of ester 41 also serves to demonstrate the possibility of employing the Claisen rearrangement for formation of a carbon-carbon double bond. The sulfur functionality serves to mask this double bond until a convenient stage is reached in the synthesis. - Oxidation of ester 41 with ~PBA 15 in high yield. - produced the epoxy ester 46 The presence of only one geometrical isomer of this epoxy ester is clearly demonstrated by NMR analysis. - that ester 41 is cleanly the (E,E)-isomer. This indicates Attempts to saponify the - epoxy ester 46 in order to obtain the corresponding acid were not encouraging. This sensitive epoxy acid was obtained in varying states · of purity and attempted purification led to extensive decomposition. The alternative approach of using the acid portion in already reduced form was also investigated. - Epoxy ester 46 was reduced under the same conditions described above and gave a mixture of two separable components (93:7). The major component was assigned the - - trans-stereochemistry 47 based on results obtained with ester 33. The minor isomer was tentatively assigned cis-stereochemistry. - Saponification of ester 47 gave a mixture of acids containing 70% of - - the unsaturated acid 48 and 30% of the conjugated isomer 49. Since the difficulty in both of these approaches arose during attempted saponification of the methyl ester in order to prepare some activated ester derivative suitable for esterif ication, saponif ication of the ester at an earlier, less sensitive stage was desirable. Hydrolysis of the dienoic ester 41 ...... proceeded without difficulty . 66 - The E_-nitrophenyl ester 44 11 of the resulting acid 43 was sufficiently -. stable to pennit partial purification by rapid chromatography on silica gel. This derivative was also readily oxidized with r.l:PBA15 to provide the epoxy ester 45. ,,..,.,, - When stirred with the alcohol 22a in 'IlfF-triethylamine, epoxy ester 45 was converted to the target ester SO AA. - through ester exchange (SCJ-IEME V). Reduction of ester SO to hydroxy ester 51 proceeded nonnally . The """' ...... minor isomer (cis?) found in the reduction of ester 46 was not detected but was probably present in the mixture. - - Initial attempts to carry this ester on to 12-methyl PGA 1 (32) met with serious difficulties. - Rearrangement and basic hydrolysis gave - the lactone 52 in only 30% yield. The unsaturated acid 43 was a major side product. - Reduction of lactone 52 with three equivalents of DIBAH proceeded smoothly but attempted aldol condensation did not produce cyclopentenone under mild (piperidinitun acetate 1 ~) or harsh (aqueous methanolic soditun hydroxide 6 ) conditions . In view of these difficulties and in face of a report that 12-methyl PGA2 was inactive , 21 the synthesis was not pursued further. Although difficulties arose in late stages of some of the syntheses described here, the potential of the ester enolate Claisen rearrangement in convergent synthesis of complex organic molecules has been demonstrated. Particularly, the compatibility of this reaction with a wide variety of functionality should make it a useful addition to the synthetic chemist's armory of reactions. 67 SQIEME v. Pre2aration and Transfonnations of Ester S0. 22a .--. + 4S a 8 2 67% so ~ b,c d-g 76% 30% Sl ~ S2 ~ aa, Et 3 N, THF, 50°, 57 hr; b, 3 equiv Li, NH 3 , THF, -78°; C, NH 4 Cl; d, LDA, THF, -78°; e, TBSCl; HMPA; f, 67°, 3 hr; g, NaOH, aq CH30H, then neutralize. 68 Experimental Section 22 Methyl Dietho~hosphinrlmethoxyacetate (7a). The procedure of Grell and Machleidt 4 was followed to prepare the phosphonate 7a from ........ methyl dimethoxyacetate: bp 1100 (0 . 3 mm) ; NMR (CDC1 3) ol.33 (t, 6H, J=7 Hz, C!:!3CH 20-), 3. S2 (s , 3H , ether CH 30-), 3.83 (s, 3H, ester CH 30-), 4. 22 (m, SH, CHC0 2- and CH 3C!::!_20); ir (neat) 17SO (C = 0), 1260 , 1120, lOlS, 970 cm -1 . Anal. Calcd for C8 H17 0 6 P: C, 40.00; H, 7.13. Fotmd C, 40.12; H, 7.08. Ethyl 2-Etho~-2-octenoate (9). A stirred suspension of 2.78 g (0.116 mol) of sodium hydride (mineral oil free) in dry THF was treated during 30 min with the dropwise addition of 30.0g (0.112 mol) of phosphonate 7b. '"""- Following the addition, the reaction mixture was stirred for an additional 30 min and then cooled to 0°. Hexanal (11.2 g, 0.112 mol) was added dropwise to this solution over a 30-rnin period. Near the end of the addition, a gurmny precipitate formed. The reaction mixture was stirred for an additional 30 min at 2S 0 and then treated with SO ml of water. Benzene extraction, 23 including an aqueous arrmonium chloride wash, followed by distillation of the residue afforded 19.5 g (81%) of a mixture (1:3) of unsaturated esters 9: bp 60 -63° (0.08 mm); NMR (CDCl3) o0 . 87 (br t, 3H, -CH2CH2C!::!_3), 1. 33 (t, 6H, J=7 Hz, -OC!:!_ 2C!:! 3) , 3.73 (br t, 2H, J=7 Hz, =COC!:!2CH 3 ) , 4.24 and 4.21 (q's, 2H, J=7 Hz, C0 2 C!:!2CH 3 ) , 6.24 and S.26 Ct's, lH, ratio 1:3, J=7 and 7.S Hz, vinylic H's); ir (CHC1 3 ) 172S, (C = 0), 1640 (C = C), 1380,1160, 1040 cm- 1 • 69 Anal. Calcd for C12 H22 0 3 : C, 67.26; H, 10.35. Folllld: C, 67.08; H, 9.80. 2-Ethoxy-2-octenyl Propanoate (11). To a suspension of 2.0 g (53 rrnnol) of lithitnn altnnintnn hydride in 120 ml of dry ether was added 10.0 g (47 rrnnol) of the esters Ao 9 over a 30-min period. Following the addition, the reaction mixture was stirred for an additional 15 min before excess hydride was destroyed by addition of ethyl acetate. Workup according to the procedure of Fieser 24 afforded 7.75 g of crude - alcohols 10 which were used without further purification. This material was treated with 15 g of propanoic anhydride in 20 ml of dry pyridine at 25° for 20 hr. Distillation of the reaction mixture gave 8.9 g - (85%) of the ester 11: bp 72-85° (0.1 mm); NMR (CDC1 3 ) 62.33 (q, 2H, J=7 Hz, CH 3 C!i.iC0 2 -), 3.65 (q, 2H, J=7 Hz, CH 3 C!i_2 0-), 4.57 and 4.62 (s's 2H, -0CH2 C=C), 4.64 and 4.86 Ct's, lH, J=7 Hz, vinylic H's); ir (neat) 1725 (C = 0), 1640 cm - 1 (C = C). Anal. Calcd for C13 H24 0 3 : C, 68.38; H, 10.59. Folllld: C, 68.58; H, 10.50. 5-Methoxy-3,5-dimethyl-4-pentyloxacyclopentan-2-one (13). A solution of 7.1 rrnnol of LICA in 20 ml of dry THF was cooled to -78°. To this rapidly stirred solution was added 1.50 g (6.6 mmol) of ester - 11 over 3 min. Following the addition, 0.850 ml (6.7 rrnnol) of TMSCl was added in one portion and the reaction mixture was stirred at -78° for an additional 3 min. The cooling bath was removed and the reaction mixture was allowed to warm to 25°. The mixture was then stirred at 70 reflux: for 7 hr to effect rearrangement. After cooling to 25° the reaction mixture was treated with 2 ml of etJiianol and sufficient methanesulfonic acid to obtain pH 1-2. Extraction 23 with petroletml ether afforded 1.6 g of a yellow oil which was evaporatively distilled - at 80° (0.2 nun) to give 1.1 g (73%) of the lactone 13. A portion of this material (400 mg) was purified further by meditml-pressure chromatography 22 on 2.5 x 50 cm of silica gel with 50% dichloromethane/benzene. Elution with 550 ml of this solvent system gave the analytical sample: NMR (CDC13) ol.10 (t, 3H, J=7 Hz, Clf3), 1.40 (d, 31-1, J=8 Hz, CJi3CH-), 3.63 (q, 2H, J=7 Hz, -CH20-); ir (neat) 1792 cm - l (C = O). Anal. Calcd for C13H2~0a: C, 68.38; H, 10.59. Found: C, 68.46; H, 10.49. 4-~thyl-5-pentyl-2-cyclopentenone (14). A solution of 450 mg - (2.0 nunol) of lactone 13 in 10 ml of dry toluene was cooled to -78°. To this stirred solution was added 2.4 ml (2.3 nunol) of DIBAH in benzene over 5 min. The reaction mixture was stirred for 30 min at -78° and then treated with 0. 5 ml of methanol and allowed to wann to 25 °. Benzene extraction 23 gave 440 mg of a colorless oil which was dissolved in 10 ml of methanol and treated with 10 ml of 5% aqueous soditml hydroxide solution. This mixture was stirred at 25° for 20 min after which benzene extraction 23 and evaporative distillation of the residue at 80° (1 IIBl1) gave 280 mg (85%) of colorless cyclopentenone !ii_: NMR (CDC1 3) d0.90 (br t, 3H, J=7 Hz, C!:!_3CH 2-), 1.22 (d, 3H, J=7 Hz, CH 3CH-), 6.14 (dd, lH, J=6 and 2 Hz, =CHC=O), 7.55 (dd, lH, J=6 and 71 and 2.5 Hz, CH=C-C=O); ir (neat) 1710 (C = 0), 1580 an Anal. Calcd for C11 H16 0: C, 79.46; H, 10.91. _1 (C = C). Found: C, 79.49; H, 10.90. 3-Methyl-2-pentyl-2-cyclopenten-l-one (15). A mixture of 118 mg - (0.711 mmol) of cyclopentenone 14 and 200 mg of potassililTl hydroxide in 10 ml of water and 5 ml of methanol was stirred at reflux for 40 min. Extraction23 with dichloromethane and evaporative distillation of the residue at 80° (1 mm ) gave 110 mg (93%) of colorless dihydrojasmone - (15): NMR 60.88 (br t, 3H, J=7 Hz, 01 3 ) , 1.2 (m, 6H), 2.05 (s, 3H, C=CCH3 ) ; ir (neat) 1700 (C = 0), 1650 cm Anal. Calcd for C1 1H16 0: -1 (C = C). C, 79.46; H, 10.91. Found: C, 79.55; H, 10.95. Meth4l 9-Cyano-2-methoxy-non-2-enoate (20a}. To a mechanically stirred suspension of 2.64 g (0.11 mol) of sodil.UTl hydride (mineral oil free) in 150 ml of dry IlfF was added 24.0 g (0.10 mol) of phosphonate - 7a over 40 min. The mixture was stirred for an additional hour and then cooled to 0°. During 30 min, the reaction mixture was treated with 13.9 g (0.1 mol) of 7-cyanoheptanal (9) while vigorous stirring was maintained. ""' Toward the end of the addition a gwnmy precipitate formed. The reaction mixture was allowed to warm gradually t o 25° over 1 hr. After cautious addition of 80 ml of water, ether extraction23 gave a slightly orange liquid which was subjected to short path dist.illation - to give 17.9 g (80%) of the cyano esters 20a, hp 120-128° (O.OlS nu11). NMR analysis indicated that this was approximately an equal mixture of 72 double bond iso~ers. A portion of this material (378 mg) was purified further by medium-pressure chrornatography 22 on 1.25 x SO cm of silica gel with 30% ether/petroleum ether at a flow rate of 1 ml/min . with 150 ml gave 174 mg of the ~-isomer. Elut i on An analytical sample was prepared by evaporative distillation at 110° (0.001 nun): NMR (CDC1 3 ) 03 . 67 (s, 3H, ether CH 30-), 3.78 (s, 3H, ester CH3 0- ), 6.23 (t, HI, J=7 Hz, vinylic H); ir (CHC1 3 ) 2250 (C=N), 1720 (C = 0) , 1651 (C = C) , 1270, 1120, 990 cm - l . Anal. Calcd for C12 H19 N0 3 : C, 63.98; H, 8. 50; N, 6. 22. Found : C, 64 . 09; H, 8.43; N, 6.26. Further elution with 10 ml of the same solvent system gave 68 mg of a mixture of the E- and Z-isomers. Continued elution with 80 ml of this solvent system gave 123 mg of the E-isomer. An analytical sample was prepared by evaporative distillation at 110° (0.001 rrnn): NMR (CDC1 3 ) 03.58 (s, 3H, ether CH 30-), 3.78 (s, 3H, ester 0-1 3 0-), 5.20 (t, lH, J=7 Hz, vinylic H); ir (CHC1 3 ) 2250 (C=N), 1725 (C = 0), 1640 (C = C), 1376, 1170, 1130 on -1 . Anal . Calcd for C12 H19 N0 3 : C, 63.98; H, 8.50; N, 6. 22. Found : C, 64.00; H, 8.48; N, 6.19. 10-!:!Ydroxy-9-methoxydec-8-enenitrile (2la~. To a vigorously stirred suspension of 685 mg (18 nunol) of sodium borohydride and 1.56 g (18 nunol) of anhydrous lithium bromide 10 in 20 ml of dry THF was - added 2.0 g (8 . 89 rrunol) of the cyano ester 20a. This mixture was stirred at 25° for 52 hr. At the end of this period, 20 ml of water was added and the reaction mixture was stirred for 40 min. After addition of 73 another 20-ml portion of water, ether extraction 23 gave 2.1 g of a colorless oil which still contained some ester (ir analysis). This material was subjected again to the same treatment and gave 1.59 g - (91%) of the crude cyano alcohol 2la as a colorless liquid. A portion of this material was purified by medium-pressure chromatography 22 on 1.25 x SO cm of silica gel with 80% ether/petroleum ether at a flow rate of 1 ml/min followed by evaporative distillation at 100° (0.001 rrnn) and gave the analytical sample: NMR (CDC1 3 ) o3.S4 and 3.65 (s, 3H total, Q-I 30), 4.13 (br s, 2H, -Q-I 2 0-), 4.6 (m, lH, vinylic H's); ir (Q-IC1 3 ) 3600 and 3470 (OH), 22SO (C = N) 1670 (C = C), 1465, 1140, 1110, lOSS, lOlS cm -1 . Anal . Calcd for C11 H19 N) 2 : C, 66.97; H, 9.71; N, 7.10. Found: C, 66.87; H, 9.S9; N, 7.01. 10-Hydroxy-9-methoxydec-8-enamide (22a). A solution of 1.97 g - (10 . 0 mmol) of the crude cyano alcohol 21a in SO ml or etha nol was a<lde<l in one portion to an ice-cooled, stirred mixture of 90 ml of 10% aqueous hydrogen peroxide and 3 ml of 40% aqueous sodium hydroxide solution . After 10 min the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hr. Dichloromethane extraction 23 gave 1.65 g (77%) of a white solid. A port i on of this mat- erial (130 mg) was purified further by medium-pressure chromatography 2 2 on l.2S x SO cm of silica gel with SO% acetone/ether at a flow rate of 1 ml/min. Elution with 26S ml of this solvent system gave 101 mg of a white solid. One recrystallization from ether containing a small amount of <lichloromcthane ~:av e the nnnlytical s ample as ;1 mixture of 74 double bond isomers: mp 51-58°; NMR (CDC1 3) 63.53 and 3.65 (s, 3H total, 01 30-), 4.09 (m, 2H, 01 20-), 4.8 (m, lH, vinylic H), 6.0 (br s, 2H, NH2); ir (CHCl3) 3700-3100 (several bands, OH, NH 2), 1675 (C = 0), 1590, 1465, 1390, 1010 cm -1 . Anal . Calcd for C11 H21 N0 3: C, 61.37; H, 9.83; N, 6.51. Found : C, 61.41; H, 9.88; N, 6.46. Eth~l 9-Srano-2-etho3f11on-2-enoate (20b). In a manner similar to - - that described for the methyl derivative 20a, phosphonate 7b and cyano aldehyde 19 were converted into a mixture of esters 20b (84%): bp 120~ 4.21 and 3.75 (q's, 4H total, J=7 Hz, 01 3C!:!_20-), 6.21 and 5.22 (t's, lH total, J=7 Hz, vinylic H); ir (neat) 2250 (C = N), 1725 (C = 0), 1640 cm- 1 (C = C). Anal. Calcd for C14 H23 N0 3: C, 66.37; H, 9.15; N, 5. 53. Found: C, 66.39; H, 9.13; N, 5.57. 9-Etho~-10-h_zdro:Zl dec-8-enenitrile (2lb) . In a manner similar - - to that described for cyano alcohol 2la, the mixture of esters 20b was reduced with lithium borohydride 10 to give the cyano alcohol 2lb (100%) : NMR (CDC1 3) 63.66 (q, 2H, J=7 Hz, o-I 3C!:!_20-), 4.12 (br s, 2H, =CCH 20-) , ir (CHC1 3) 3600 and 3470 (OH), 2240 (C = N), 1 1665 (C = C), 1385, 1105, 1050, 1010 cm- . 4. 4 (m, lH, vinylic H); Anal. Calcd for C12 H21 N0 2 : C, 68.25; H, 10.09; N, 6.60. C, 68 .21; H, 10 . 02; N, 6.63. Fotmd: 75 9-Ethoxy-10-hydroxydec-8-eriamide - (22b). In a manner similar - to that described for hydroxy amide 22a, the cyano alcohol 2lb was con verted into -- the hydroxy amide 22b (72%): NMR (CDC1 3) 63.15 (br s, lH, OH), 3.68 (q, 2H, J=7 Hz, CH 3C!:!_20-), 4.13 and 4.10 (s, 2H total, -C!:!_20H), 4.47 and 4.76 (t, lH total, J=7.5 and 8 Hz, vinylic H), 6.2 (br s, 2H, NH 2); ir (CHC1 3), 3700-3150 (several bands, OH, NH 2 ) , 1675 (C = 0, C = C), 1590 cm -1 . Anal. Calcd for C12 H23 N0 3: C, 62.85; H, 10.11; N, 6.11. FolUld: C, 62.79; H, 10 . 17; N, 6.14. 9-Cyano-2-ethoxy-2-nonenyl (_!D-3-Decenoate (16). To a solution of 1.40 g (6.0 rnmol) of E.-nitrophenyl trifluoroacetate 11 in 3 ml of dry pyridine was added 1.0 g of (_!D-3-decenoic acid 25 . stirred for 2 hr at 25°. This mi xture was Pentane extraction 23 including an acid wash and a base wash, gave 1.37 (80%) of E.-nitrophenyl (~)-3-decenoate which was not purified further: (31_) NMR (CDC1 3) 62.07 (m, 2H, =CCH 2) , 3. 30 (d, 2H, J=5 Hz, =CCH 2C0 2-), 5.65 (m, 2H, CH=CH), 7.25 (d, 2H, J=8 Hz, aromatic H's), 8.25 (d, 2H, J=8 Hz, aromatic H's); ir (neat) 1765 (C = 0), 1620, 1595, 1530, 1495, 1350, 1115 cm - 1 . - This crude E.-nitrophenyl ester 23 was dissolved in 3 ml of dry triethylarnine and was treated with 1.3 g (6.1 rnmol) of the cyano alcohol ........... 2lb. This mixture was stirred at 25° for 16 hr . Pentane extraction,23 including a base wash, gave 1.6 g of an oil which was filtered through 7 g of silica gel with benzene to give 1.14 g (50%) of cyano ester 16 as a colorless oil: .4J'a NMR (CDC1 3) 62 . 96 (br d, 2H, J=4 Hz, -CH 2C0 2-), 3.63 (q, ZH, J=7 Hz, CH 3C!:!_20-), 4.48 (s, and t, 3H, J=7 Hz, 76 -OCH 2 C=o-I-), 5.50 (m, 2H, CH=CH); ir (neat) 2250 (C = N), 1737 (C = 0), 1668 cm- 1 (C = C). Anal. Calcd for C22 H37 N0 3 : C, 72.69; H, 10.26; N, 3.85. Found: C, 72.69; H, 10.27; N, 3.78. 9-Carbamoyl-2-ethoxy-2-nonenyl (E)-3-decenoate (17). The E_-nitrophenyl ester 23 ...... (4.8 nnnol) was added to 1.0 g (4.4 nnnol) of the hydroxy amide ........ 22b in 2 ml of dry triethylamine. stirred for 36 hr at 25°. This mixture was Ether extraction, 23 including a base wash, gave a yellow oil which was purified by chromatography on lOg of silica gel with 300 ml of benzene, then 200 ml of dichloromethane and finally 800 ml of ether. The ether fraction contained 1.4 g (83%) of a slightly yellow oil which solidified upon standing. A portion of this material was recrystallized from petrolel.Ull ether to afford the analytical sample: mp 53-54°; NMR (CDC1 3 ) 83.03 (d, 2H, J=5 Hz, CH 2 C0 2 -), 3.68 (q, 2H, J=7 Hz, o-I 3 C!:!_2 0-), 4.60 (sand t, 3H, J=7 Hz, o-I 2 C=o-I-), 5.53 (m, 2H, o-I=o-I), 5.8 (br, 2H, NH 2 ); ir (o-IC1 3 ) 1725 (ester C = 0), 1675 (amide C = 0), 1590, 1115, 1060, 965, 910 cm Anal. Calcd for C22 H39 N0 4 : Found: -1 . C, 69.25; H, 10.30; N, 3.67. C, 69.34; H, 10.27; N, 3.64. 4-(6-Carbamoylhexyl)-5-ethoxy-5-methyl-3-(1-octenil)-oxacrclopentan-2-one (24). A solution of 1.64 rrnnol of LICA in 3 ml of dry THF was cooled to -78°. To this rapidly stirred mixture was added a solution of 206 mg (0.54 nnnol) of ester 17 in 1 ml of dry THF over ~ 35 sec. After an additional 2 min at -78°, 0.250 ml (1.95 nnnol) of 77 TMSCl was added in one portion. The reaction mixture was stirred for an additional 3 min at -78° and then allowed to warm to 25°. The mixture was then stirred at reflux for 3.5 hr to effect rearrangement. After cooling to 25°, the mixture was treated with 0.1 ml of ethanol and sufficient methanesulfonic acid to give pH 1-2. Irrnnediate dichloro- methane extraction 23 afforded 227 mg of a yellow oil. This material was purified by medium-pressure chromatography 22 on 1.25 x 50 cm of silica gel with 20% acetone/benezene. Elution with 300 ml of this - solvent mixture afforded 141 mg (68%) of the lactone -amide 24 as a colorless oil: NMR (COC1 3 ) 61.60 (s, 3H, GI 3 C-(0) 2 - ) , 3.66 (q, 2H, J=7 Hz, CH 3 C!:!_2 0-), 5.5-6.3 (br m, 4H, CH=GI and NH 2 ) ; ir (CHC1 3 ) 37003150 (several bands NH 2 ) , 1765 (lactone C = 0), 1675 (amide C = 0), 1590 cm- 1 Anal. Calcd for C22 H39 N0 4 : C, 69.25; H, 10.30; N, 3.67. Found : C, 69.10; H, J0.30; N, 3.71. (E)-4-Decenoyl Chloride (25) . A solution of 1.37 g (8.05 rrnnol) "' of (~)-4-decenoic acid 3 in 15 ml of dry benzene was treated with 1.14 ml (1.90 g, 16 rrnnol) of thionyl chloride . at reflux for 1 hr. This mixture was stirred After the reaction mixture had cooled to 25°, the benzene and excess thionyl chloride were removed by rotary evaporation at reduced pressure followed by addition and similar removal of a second 15-ml portion of benzene . The residue was evaporatively distilled at 50-55° (0.05 rrnn) and gave 1.41 g (93%) of the acid chloride as a colorless liquid: NMR (COC1 3 ) 62 . 95 (m, 2H, C-2 H's), 5.45 (m, 2H, GI=GI); ir (GIC1 3 ) 1800 (C = 0), 1405, 970, 915, 730, 685 an -1 78 ?-Carbamoyl-2-methoxy-2-nonenyl (lgl-4-Decenoate (18). A solution -- of 1.37 g (6 . 37 rrnnol) of the hydroxy amide 22a and 3.53 ml (2 . 55 g, 25 rrnnol) of dry triethylamine in 25 ml of dry dichloromethane was cooled to o0 • To this stirred solution was added 1.20 g (6.37 rrnnol) of the acid chloride 25 in 10 ml of dichloromethane. The reaction mixture was allowed to warm to 25° over 1 hr and then was stirred for 11 hr . Extraction 23 with 10% dichloromethane/ether, including a base wash , gave 2.02 g of a yellow oil which crystallized upon standing. This material was purified by medium-pressure chromatography 2 2 on 2.5 x 50 cm of silica gel with 40% acetone/ether at a flow rate of 2 ml/min. After elution with 210 ml of this solvent system, the next - 160 ml afforded 1.69 g (72%) of the ester 18 as a white waxy solid containing two isomers. A portion of this material was recrystallized from hexane and gave white platelets: mp 52 . 5-60°; NMR (CDC1 3 ) 83.47 and 3.55 (s, 3H total , CH 3 0) , 4.57 (m , 21-1, -ClhO-), 4.8 (m , HI, enol ether vinylic H), 5. 42 (m , 2, 01=CH), 5. 7 (br , 2H, NH 2 ) ; ir (CHC1 3 ) 3540, 3500 and 3420 (NH 2 ), 1730 (ester C = 0), 1675 (amide C = 0), 1590, 1160 , 1120 , 1070 , 970 cm Anal. Calcd. for C21 H3 1N0 4 : Found: - l . C, 68.63; H, 10.15 ; N, 3.81. C, 68.64; H, 10.13; N, 3.84. 4- (6-Carbamoylhe.!11) -5-metho!l:-5-methyl-3- (2-octenyl) -oxacr clopentan-2-one (27). A solution of 1.5 rrnnol of LDA in 3.0 ml of dry THF was cooled to -78° . To this rapidly stirred solution was added 79 - 184 mg (0.5 mrnol) of the ester 18 in 1 ml of TI;F over 1 min. After an additional 2 min at -78°, 1.0 ml (1.52 mrnol) of TBSCl in HMPAwas added in one portion. This mixture was stirred at -78° for an ad<li- tional 2 min after which the cooling bath was removed and the reaction mixture was allowed to warm to 25° over 20 min. was then stirred at reflux for 3.5 hr. 1he reaction mixture Extraction 23 with 75% ether/ petroleum ether afforded 369 mg of a nearly colorless oil. This oil was dissolved in 3 ml of 'I1IF and 1 ml of methanol; one drop of methanesulfonic acid was added and the mixture was stirred for 35 min at 25°. Extraction 23 with 75% ether/petroleum ether, including a base wash, gave 198 mg of a colorless oil. This material was purified by medium-pressure chromatography 22 on 1.25 x 50 cm of silica gel with 25% acetone/ether at a flow rate of 1 ml/min. After elution with 110 ml of this solvent system, the next 10 ml gave 45 mg of a mixture of compounds which by NMR analysis appeared to contain 50% of the desired lactone. Continued elution with 65 ml of the same solvent system gave 102 mg - (56%) of a mixture of diasteriomers of the lactone 27 as a colorless oil: NMR (CDC1 3 ) ol.35 (br s, methylenes), 1.43 and 1.53 (s, 3H total, CH 3 C-(0) 2 - ) , 3.33 (br s, 3H, 0-1 3 0-), 5.5 (br m, 4H, o;=o-I and N!-1 2 ): ir (GIC1 3 ) 1765 (lactone (C = 0), 1680 (amide C = 0), 1590, 1385, 975, 910 crn- 1 Anal. Calcd for C21 H37 N0 4 : Found: C, 68.63; H, 10.15; N, 3.81. C, 68. 72; H, 9.99; N, 3.62. 5-(6-Carbamoylhexyl)-4-(2-octenyl)-2~c~clogentenone A. Reduction with DIBAH. (282. A solution of 102 mg (0.278 nnnol) of 80 - lactone 27 in 4 ml of dry ether was cooled to -78°. To this stirred solution was added 0. 855 ml (0 .612 rrrrnol) of a solution of DIBAH in benzene over a period of 3 min. The reaction mixture was stirred at -78° for an additional 30 min, then 0.15 ml of methanol was added to the mixture and the cold bath was removed. After the reaction mixture had warmed to 25°, 0.15 ml of water and 0.2 g of Celite were added . The reaction mixture was stirred vigorously for 15 min . Anhy- droIB sodium sulfate (0. 2 g) was again subjected to vigorous stirring for 15 min. The reaction mixture was then filtered with the aid of 75 ml of ether. The filtrate was evaporated at reduced pressure and gave 95 mg (92%) of a crude lactol which was not purified further. B. Aldol Condensation. A solution of 69 mg (0.187 rrnnol of the crude lactol in 5 ml of ethanol and 5 ml of 5% aqueous sodium hydroxide solution was stirred for 20 min at 25°. gave 53 mg of a colorless oil. Ether extraction 23 TI1is material was purified by medium- pressure chromatography 22 on 1.25 x 50 cm of silica gel with 30% acetone/ ether at a flow rate of lml/min. After elution with 120 ml of this solvent system, continued elution with 35 ml afforded 33 mg (51%) of the cyclopentenone ........ 28 as a colorless oil: NMR (CIX:l 3 ) 62.05 (t, 2H, J=7 Hz, CH 2 C=O), 5.42 (m , 2H , CH=CH), 5.73 (m , 2H, NH 2) , 6.10 (dd , lH, J=6 and 1 Hz, =0-1-C=O) , 7.56 (dd, 11-l, J=6 and 2 Hz CH=C-C=O); ir (CHC1 3 ) 3550-3100 (several bands, NH 2 ) , 1685 (enone and amide C = 0), 1590, 970 an -1 ; uv(EtOH) \max= 219 mµ (t:= 10,000). Anal. Calcd for C20 H33 N0 2 : C, 75.05; H, 10 .47; N, 4.41. C, 75.1~; H, 10 .41; N, 4.38. Found: 81 4-~6-Carboxyhexyl)-5-metho22'._-5-methxl-3-(2-octenrl)­ oxacyclopentan-2-one (29). A solution of 2.04 rrnnol of LDA in 7 ml of dry THF was cooled to -78° . To this stirred solution was added 1.8 ml - of dry HMPA followed by 250 mg (0 . 679 nunol) of the ester 18 in 2 ml of 1HF over 4 min . The reaction mixture was stirred for an additional 2 min and then 0.59 ml (2.04 rrnnoD of TBSCl in hexane was added. After an additional 2 min at -78° , the cold bath was removed and the reaction mixture was allowed to warm to 25°. The mixture was then stirred at reflux for 3 hr. Extraction 23 with 75% ether/petroleum ether gave a non-mobile oil. This material was stirred at reflux in a solution of 1. 2 g sodium hydroxide, 6 ml of water and 15 ml of methanol for 16 hr. The cooled reaction mixture was poured into 30 ml of water and extracted with three 25-ml portions of ether (extracts discarded). The basic solution was cooled to 0° and acidified by addition of 90 ml of 0.4 N H2 S0 4 with stirring . of an oil. Dichloromethane extraction 23 gave 220 mg This material was purified by medium-pressure chromate- graphy 22 on 1. 25 x 50 cm of silica gel with petroleum ether : dichloromethane : 1HF : acetic acid= 50:10:3:2 at a flow rate of 1 ml/min. After elution with 60 ml of th i s solvent system, continued elution with 50 ml gave 162 mg (65%) of a mixture of diasteriomers of the - lactone-acid 29 as a colorless oil: NMR (CDC1 3 ) ol.43 and 1.53 (s, 3H total, G-1 3 C-(0) 2 -), 3.36 (s, 3H, G-1 3 0-), 5.65 (m, 2H, CH=CH); ir (o-IC1 3 ) 1765 (Jactone C = OJ, 1710 (acid C = 0), 1380, 975, 910 cm -1 • 82 Anal. Calcd for C21 H36 0 5 : C, 68.45; H, 9.85. Fot.md: C, 68.42; H, 9. 72. 5-(6-Carboxyhexyl)-4-(2-octenyl)-2-cyclopentenone (30). A. Reduction with DIBAH. A solution of 168 mg (0.450 rmnoD of - the lactone-acid 29 in 15 ml of dry ether was cooled to -78°. To this stirred solution was added 1.17 ml (1. 01 rrnnol) of DIBAH in benzene over a 4-min period. The reaction mixture was then stirred at -78° for an additional 30 min. The mixture was then treated with 0.6 ml of methanol to quench excess hydride and was stirred for an additional 5 min at -78°. The reaction mixture was then rinsed into a mixture of 5 ml of acetic acid and 10 g of ice with 25 ml of ether. This mixture was stirred for 5 min, after which ether extraction 23 afforded 166 mg (quantitative crude yield) of a keto-aldehyde: NMR (CDC1 3 ) ol.33 (m, -Gl 2 - ) , 2.16 and 2.23 (s, 3I-I total, o-I 3 C = 0), 5.38 (m, 2H, CH GI), 9.41 (br s, lH, C0 2 H), 9.69 (m, lH, CHO). B. Aldol Condensation. This keto-aldehyde was dissolved in 15 ml of dry ben::ene and was treated with 5.7 µl of acetic acid and 9.9 pl of piperidine. This mixture was stirred at reflux with continuous removal of water by means of a Dean -Stark apparatus charged with 4A molecular sieves. After 4.75 hr, TLC analysis indicated that some starting keto-aldehyde remained. The reaction mixture was again treated with 5.7 µl of acetic acid and 9.9 µl of piperidine and reflux was continued for 2 hr. Ether extraction, 23 including a wash with 20% aqueous sodium dihydrogen phosphate solutjon, gave 197 mg or a 83 slightly yellow oil. Purification by PTLC 22 ' 26 on 13 x 20 x 0.2 on of silica gel with hexane : dichloromethane : 1HF : acetic acid = 30:10:5:3 afforded 126 mg (86% from lactone ....... 29, Rf= 0.23-0.38) of cyclopentenone 30 .,...,, as a colorless oil: NMR (CDC1 3 ) 85.44 (m, 2H, 01 = 01), 6.15 (dd, lH, J=6 and 1 Hz, =CHC=O), 7.60 (dd, lH, J=6 and 2 Hz, 01=CC=O), 10.07 (br s, lH, C0 2 H); ir (01Cl 3 ) 3400-2600 (C0 2 H), 1705 (enone and acid C = 0), 1590, 950 on -1 ; uv(EtOH) Amax= 219 mµ (E= 9400). Anal. Calcd for C20 H32 0 3 : C, 74.96; H, 10.06. Found: C, 74.90; H, 9.90. 3-(~;Carbo:xyhe~l)-2,5-d~e!ho~-2-methyl-4 :(2-octenyll­ oxacyclopentane (31). A solution of 133 mg (0.361 rnrnol) of the crude lactol, which resulted from reduction of lactone lZ_ (vide supra), in 7 ml of methanol was cooled to 0°. To this solution was added one drop of methanesulfonic acid and the reaction mixture was stirred at o0 for 3 hr. Ether extraction, 23 including a base wash, gave 128 mg (93%) of a slightly brown oil. A portion of this material (75 mg) was purified by mediLU11-pressure chrornatography 22 on 1.25 x 50 cm of silica gel with 30% acetone/ether at a flow rate of 1 ml/min. After elution with 135 ml of this solvent, continued elution with 125 ml afforded 53 mg of a mixture of several diasteriomers of the bis acetal 31 as ~ a colorless oil: NMR (CDC1 3 ) 3.27, 3.32, 3.37 and 3.40 (s, 01 3 0), 4.65 (m, lH, -OCI-D-), 5.43 (m, 2H, 01=CH), 5.68 (m, 2H, NH 2 ); 1675 (amide C = 0), 1590, 1380, 1100, 975 cm Anal. Calcd for C22 H41 N0 4 : C, 68.91; H, 10.76; N, 3.66. -1 . C, 68.89; H, 10.77; N, 3.65. Found: 84 Preparation of Cyclopentenone 30 from Bis Acetal 31. A solution of 128 mg (0.334 nnnol) of the crude bis acetal 31 in 25 ml of methanol and 8 ml of 20% aqueous sodil.UTl hydroxide solution was stirred at reflux for 8 hr. The reaction mixture was poured into 150 ml of pH 7 buffer (Beckmann) containing a small amount of brornothyrnol blue. The blue solution was neutralized by dropwise addition of cone hydrochloric acid at 0° until a light green color was obtained. extraction 23 gave 95 mg of a brown oil. This material was partially purified by filtration through 15 g of silica gel. of ether gave 48 mg of art oil. of 1HF and 3 ml of water. Dichloromethane Elution with 40 ml This material was dissolved in 7.5 ml To this solution was added 0.3 ml of cone hydrochloric acid and the mixture was stirred at 25° for 1.5 hr. At the end of this period, 0. 75 ml of 40% aqueous sodium hydroxide solution and 3 ml of methanol were added . stirred at 25° for 25 min. The reaction mixture was then poured into 20 ml of 5% hydrochloric acid . orange oil. The reaction mixture was Ether extraction 23 gave 44 mg of an Chromatography of this material on 15 g of silica gel with 30 ml of 75% ether/petroleum ether, 30 ml of 90% ether/petrolel.UTl - ether, and finally 60 ml of ether gave 15 mg (14% from lactone 27) of - the cyclopentenone acid 30 . Isopropyl 4,5-Epoxy-2-hexenoate (33) . A solution of 5.8 g (37.7 rrnnol) of isopropyl sorbate in 100 ml of dichlorornethane was cooled to o0 • To this solution was added 11.5 g (56.5 nnnol) of 85% 85 ~-chloroperbenzoic acid during a 10-min period. Following this addition, the reaction mixture was stirred at o0 for 30 min and at 25° for 4 hr. Excess peracid was then destroyed by dropwise addition of 10% aqueous sodium bisulfite solution and the product was isolated by ether extraction, 23 including a base wash. The residual liquid was purified by chromatography on 200 g of silica gel. After elution with 500 ml of 10% ether/petroleum ether and then 250 ml of 20% ether/petroleum ether, continued elution with the latter - solvent system gave 4.9 g (76%) of the epoxy ester 33. An analytical sample was obtained by preparative VPC 22 (200°, 1/4 in. x 8 ft. 10% Carbowax 20 M, 60 ml/min, thermocouple) followed by evaporative distillation at 40° (0.08 mm): NMR (CDC1 3) ol.25 (d, 6H, J=6 Hz, (CH3)2C), 1.35 (d, 3H, J=6 Hz, C-6 H), 2.95 (q of d, lH, J=5 and 2 Hz, C-5 H), 3.13 (dd, lH, J=6 and 2 Hz, C-4 H), 5.07 (septet, lH, J=6 Hz, (CH 3 ) 2 C!:!_O-), 6.07 (d, lH, J=l5 Hz, C-2 H), 6.67 (dd, lH, J=l5 and 6 Hz, C-3 H); ir (CHC1 3 ) 1710 (C = 0), 1660 (C = C), 1110, 975, 915, 940, 830 cm- 1 Anal . Calcd for C 9 H 1 ~0 3 : C, 63.51; H, 8.29. Fotmd: C, 63.52; H, 8.36. Reduction of Ester 33. A. With Lithium in Ammonia. A mixture of 24 ml of dry THF and 96 ml of dry ammonia was cooled to -78° . To this stirred solution was added 63 mg (9 mmol) of lithium wire in 6 freshly cut pieces. - After 10 min at -78°, a solution of 510 mg (3 mmol) of the ester 33 in 2 ml of dry THF was added to the rapidly stirred reaction mixture as fast as 86 possible. After 40 sec, the blue color faded and 9 g of solid annnonilllil chloride was added. Stirring was continued at -78° for 2 min, after which the cooling bath was removed and ammonia allowed to evaporate over 4 hr. Dichloromethane extraction 23 gave 480 mg of a colorless oil which was purified further by chromatography on 15 g of silica gel with 50% ether/petrolelUil ether. After elution with 40 ml of this solvent mixture, continued elution with 80 ml gave 410 mg (79%) of - - a mixture of alcohols 36a and 37a. Analysis by VPC 22 (160°, 1/4 in x 8 ft. 10% Carbowax 20 M, 60 ml/min, thermocouple) indicated that the mixture contained an 89:11 ratio of isomers: NMR (CDC~ 3 ol.22 (d, 6H, J=6 Hz, (CH 3 ) 2 C), 1.25 (d, 3H, J=6 Hz, C-6 H's), 2.3 (br, lH, OH), 3.00 (m, 2H, C-2 H's), 4.27 (m, lH, C-5 H), 5.00 (septet, lH, J=6 Hz, (CH 3 ) 2 C!::!_-), 5.67 (m, 2H, C-3 Hand C-4 H); ir (CHC1 3 ) 3600 and 3400 (OH), 1720 (C = 0), 1375, 1110, 1060, 970 cm Anal. Calcd for C9 H16 0 3 : - 1 . C, 62.77; H, 9.36. Found: C, 62.70; H, 9.44. Isopropyl (E)-5-(tert.-Butyldimethylsilyloxy)-3-hexenoate (36b); Isopropyl (Z)-5-(tert.-Butyldimethylsilyloxy)-3-hexenoate (37b2. 'S Following the procedure of Corey, 18 a mixture of 462 mg (2.69 mrnol) of - - the alcohols 36a and 37a from the lithilllil in ammonia reduction above, 483 mg (3.22 mrnol) of TBSCl, and 457 mg (6.73 rrunol) of imidazole in 5 ml of dry DMF was stirred at 25° for 17 hr. Pentane extraction 23 gave 731 mg of a slightly yellow oil which was filtered through 15 g of silica gel with 80 ml of 5% ether/petrolelUil ether. 526 mg (68%) of a colorless oil. This afforded Analysis by VPC 22 (160 , 1/4 in x .87 8 ft 10% Carbowax 20 M, 60 ml/min, thennocouple) indicated that this consisted of two isomeric components. rention time of 11. 5 min; of 13.0 min. The minor isomer (10%) had a the major isomer (90%) had a retention time These isomers were separated by medit.nn-pressure chromato- graphy22 on 0.9 x 60 cm of silica gel with 5% ether/petrolet.nn ether at a flow rate of 0.5 ml/min. The more mobile component was the minor - isomer which was assigned the Z-stereochemistry 37b. An analytical sample was prepared by evaporative distillation at 50° (0.05 mm): (d, 3H, J=6 Hz, C-6 H's), 1.22 (d, 6H, J=6 Hz, (CH 3) 2C), 1.37 (d, 2H, J=5 Hz, C-2 H's), 4.5 (m, lH, C-5 H), 5.00 (septet, lH, J=6 Hz, (CH3)2C!:!_-), 5.55 ·cm, 2H, C-3 Hand C-4 H); 1260, 1110, 915, 875, 835 cm- 1 , Anal. Calcd for C15 H30 0 3Si: ir (CHCl3) 1725 (C = 0), no band at 970 cm- 1 • C, 62.89; H, 10.55. Fotmd: C, 62.94; H, 10. 58. The less mobile component was the major isomer and was assigned - the E-stereochemistry 36b. - An analytical sample was prepared by evaporative distillation at 50° (0.05 mm): NMR (CDC1 3) 60.05 (s, 6H, (CH 3) 2Si), 0.90 (s, 9H, (CH3)3CSi), 1.20 (d, 3H, J=6 Hz, C-6 H's), 1.22 (d, 6H, J=6Hz, (CH3)2C), 2.98 (d, 2H, J=5Hz, C-2H's), 4.27 (m, lH, C-5 H), 5.02 (septet, lH, J=6 Hz, (CH 3) 2C!:!_0-), 5.65 (m , 2H, C-3 Hand C-4 H); ir (CHC1 3 ) 1720 (C=O), 1260, 1110, 970, 910, 835 an- 1 • Anal. Calcd for C15 H30 0 3Si: 63.00; H, 10.58. C, 62.89; H, 10.55. Found: C, 88 Reduction of Ester 33. B. With Soditnn in HMPA-1HF, Followed by Silylation with TBSCl. A solution of soditnn in 1-IMPA-'IHF was prepared according to the procedure of House. 17 Titration of an aliquot of this solution with sec-butanol in xylene indicated that it was 0.35 M in soditnn. Add i t i on of a second aliquot to water followed by titration with standard HCl to a phenolphthalein endpoint indicated that the solution was 0.32 M in total base. - A solution of 170 mg (1 rmnol) of ester 33 in 13.7 ml of TI!F was cooled to -78°. To this rapidly stirred solution was added 5.88 ml (2.0 mmol) of the Na-HMPA-'IHF solution in one portion. occurred after 70 sec. Deco l orization After an additional 2 min at -78° the yellow solution was treated with 0.65 ml (2.2 mmol) of TBSCl in hexane and was stirred at -78° for an additional 2 min. The cooling bath was then removed and the r eaction mixture was stirred at 25° for 20 min . Pentane extraction23 gave a yellow oil which was dissolved in 5 ml of 1HF and treated with 1 ml of 70% aqueous acet i c acid solution. This solution was stirred at 25° for 1 hr to effect hydrolysis of the silyl ketene acetal. Pentane extraction, 23 including a base wash, gave a nearly colorless oil which was purified by chromatography on 10 g of silica gel with 10% ether/petroleum ether. Elution wi th 35 ml of this - solvent mixture gave 113 mg (39%) of a mi xture of silyl ether s 36b and - 37b. Analysis by VPC 22 (160°, 1/4 in x 8 ft 10% Carbowax 20 M, 60 ml/ min, thermocouple) indicated that this material consisted of a mixture -- -- of ~-silyl ether 37b (40%) and E-silyl ether 36b (60%). - 89 C. With Sodium in HMPA-11-IF Followed bl Protonation. of sodium in HMPA-11IF 17 was prepared as in B above. A solution Titration of total J\o base with standard HCl indicated that the solution was 0.256 M in sodium. - A solution of 170 mg (1 . 0 rronol) of ester 33 in 43 ml of dry TI-IF and 4 ml of dry HMPA was cooled to -78°. To this rapidly stirred solution was added 11.7 ml (3.0 rronol) of the Na-HMPA-11-IF solution in one portion. The blue color persisted and was discharged after 1 min by addition of 9 g of solid ammonium chloride. After an additional 2 min at -78°, the reaction mixture was allowed to warm to 25° over 30 min. Pentane extraction gave 127 mg of a yellow oil which was purified by chromatography on 15 g of silica gel with 50% ether/petroleum ether. After elution with 54 ml of this solvent mixture, continued - elution with 40 ml gave 73 mg (42%) of a mixture of alcohols 36a and - 37a. D. With Zinc in HMPA-11-IF. 3 A mixture of 340 mg (2.0 mmo l ) of - epoxy ester 33, 600 mg (4 mmol) of TBSCl, and 0. 5 g of zinc dust i n 10 ml of dry TI-IF and 2. 5 ml of dry HMPA was stirred at reflux for 16 hr . Pentane extraction 23 gave a colorless oil. NMR analysis indicated - that this material consisted of only the starting ester 33 . Enolization of !!(dro~ Esters 36a and 37a. of LDA in 20 ml of dry TI-IF was cooled to -78°. added 4.0 ml of dry HMPA. A solution of 2.2 rronol To this solution was This rapidly stirred solution was treated with the dropwise addition of 172 mg (1.0 mmol) of a mixture of the - hydroxy ester 36a (90%) and 37a (10%) in 2 ml of dry TI-IF over 4 min . ,_..,, 90 Following the addition, the reaction mixture was stirred at -78° for an additional 2 min and then 0.65 ml (2.2 nunol) of TBSCl in hexane was added in one portion. After an additional 2 min, the reaction mixture was allowed to warm to 25 and was stirred for 30 min. Pentane extraction 23 gave a slightly yellow oil which contained none of the - starting esters and was identified as the ketene acetal 35 (NMR analysis). This material was dissolved in 5 ml of 'IHF and was treated with 1 ml of 70% aqueous acetic acid. After 1.5 hr, VPC 22 analysis (160°, 1/8 in x 6 ft, 4% SE-30, 60 ml/min, flame ionization) employing hexadecane as an internal standard (corrected for sensitivities) indicated - - that the siloxy esters 36b and 37b were present in 56% yield. VPC 2 2 analysis (160°, 1/4 x 8 ft, 10% Carbowax 20 M, 60 ml/min, thermocouple) demonstrated that the mixture consisted of 90% of the E-ester 36b and -- 10% of the Z-ester 37b. Enolization of the Siloxy Esters 36b and 37b. A solut i on of 0.6 nunol of LDA in 5 ml of dry 1HF was cooled to -78° and 1. 0 ml of dry HMPA was added. To this rapidly stirred mixture was added a - solution of 143 mg (0.5 nunol) of a mixture of the silyl ether 36b (90 %) - and 37b (10%) and 90 mg (0 . 6 rnrnol) of TBSCl in 0.5 ml of dry TI-IF over 4 min. After an additional 2 min at -78° , the reaction mixture was allowed to warm to 25° and was stirred for 30 min . Pentane extraction 23 gave a slightly yellow oil which contained none of the starting esters - - The ketene acetal was hydrolized and the were present in 64 %yield. This consisted of ester 36b (90%) and ester 36b or 37b (NMR analysis). reaction mixture analyzed as described above. 37b (10%). ~ 1he silyoxy esters - 91 Methyl (£)-2-Methyl-2-(phenylthio)-4-decenoate (40). A solution of 3.37 g (11.53 rrnnol of (£)-2-methyl-2-(phenylthio)-4-decenoic aci<l 3 in 40 ml of dry HMPA was treated with 353 mg of sodium hydride (mi neral oil free) in small portions over a 10-min period. Following the addition, the reaction mixture was stirred at 25° for 1.25 hr and then treated with 2.49 ml (S.68 g, 40 rrnnol) of iodomethane in one portion. This mixture was stirred at 25° for 3 hr and then diluted wi th 100 ml of 5% hydrochloric acid solution. Ether extraction, 23 including a was h with 10% aqueous sodium thiosulfate solution, gave 3.40 g of a s l ight l y yellow oil. This material was purified by chromatography on 170 g of silica gel with 5% ether/petroleum ether. After elution with 540 ml of this solvent system, continued elution with 360 ml gave 3.21 g (91 %) - of the methyl ester 40 . An analytical sample was prepared by evapora - tive distillation at 120° (0 . 05 rrnn): NMR (Cix:l 3) 1.38 (s , 3H , CH 3 ) , 2.00 (m , 2H), 1.8-2.9 (4H), 5. 43 (m, 2H, CH=CH), 7 .4 (m , SH, C6 1! 5 ) ; ir (CHC1 3) 1725 (C = 0), 1435, 1375, 1025, 970 cm Anal. Calcd for C1aH2502S: - 1 . C, 70.56; H, 8.55; S, 10.46 . Found: C, 70.62; H, 8.62; S, 10.49. Methyl (~_,£)-2-Methyl-2,4-decadienoate Methylene-4-decenoate (42) . (41); Methyl (~)-2- A solution of 3. 0 g (9 . 80 rrnnol) of the - a.-(phenylthio) ester 40 in 125 ml of dichloromethane was cooled to o0 • To this stirred solution was added a solution of 1.99 g (9.80 mmol) of 85% !!!_-chloroperbenzoic acid in 25 ml of dichloromethane over a perio<l 92 of 1 hr. Following the addition, the reaction mixture was stirred at 0° for an additional hour. Ether extraction, 23 including a base wash, gave a mixture of sulfoxides. This material was dissolved in 65 ml of carbon tetrachloride and was stirred at 60° for 2 hr. The reaction mixture was cooled to 25° and the solvent was removed at reduced pressure. The residue was partially purified by passage through 100 g of silica gel with 200 ml of 30% ether/petroleum ether and afforded 2.0 g of a colorless oil. VPC 22 analysis (200°, 1/4 in x 8 ft 10% Carbowax 20 M, 60 ml/min, thermocouple) indicated that this material consisted of only two volatile components. (retention time The minor component 3.5 min) accounted for 22% of the mixture and the major component (retention time= 7.5 min), 78%. These isomers could be separated by medium-pressure chromatography 22 on 2.5 x SO cm of silica gel with 2% ether/petroleum ether at a flow rate of 2 ml/min. After elution with 380 ml of this solvent system, continued elution with 300 ml gave 387 mg (20%) of the minor component which was identi- - fied as the a-methylene ester 42. An analytical sample was prepared by evaporative distillation at 60° (0.1 nnn): NMR (CDC1 3 ) o0.5-1.5 (9H), 2.0 (m, 2H, C-6 H's), 3.0 (m, 2H, C-3 H's), 3. 77 (s, 3H, CH 3 0), 5.50 (m, 3H, vinylic H's), 6.15 (br s, lH, vinylic H ~to ester); ir (CHC1 3 ) 1715 (C = 0), 1630 (C = C), 1435, 1140, 975, 950 cm Anal. Calcd for C12 H20 0 2 : C, 73.43; H, 10.27. Found: -1 C, 73.38; H, 10.18 . After elution with an additional 20 ml of the same solvent system, continued elution with 430 ml gave 1.411 g (73%) of the major isomer which was identified as the fully conjugated isomer 41. -. An 93 analytical sample was prepared by evaporative distillation at 60° (0 . 05 nnn): NMR (COC1 3 ) oO. 7-1.6 (9H), 1. 90 (br s, 3H , vinylic CH 3 ) , 2.2 (m, 2H, C-6 H's), 3.72 (s, 3H, CH 3 0-), 6.23 (m, 21-1, C-4 11 and C-5 H), 7.13 (br d, lH, J=8 Hz, C-3 H); ir (CHC1 3 ) 1700 (C = 0), 1640 and 1610 (C = C), 1435, 1110, 970 an- 1 • Anal. Calcd for C12 H20 02 : C, 73.43; H, 10 . 27. Found: C, 73 . 42; H, 10.16. In a separate experiment it was possible to separate and independently pyrolize the two diastereomeric sulfoxides. The mixture of sulfoxides from oxidation of 2.0 g (6.54 rrnnol) of the ester 40 was .AA subjected to chromatography on 200 g of silica gel. After elution with 400 ml of 30% and 300 ml of 40% ether/petrolelUTl ether, continued elution with 225 ml of 50% ether/petroleum ether gave 712 mg of the more mobile sulfoxide contaminated with decomposition products. Further elution with 150 ml of the same solvent mixture gave 346 mg of the less mobile sulfoxide, also contaminated with decompos i tion products. Rapid rechromatography on 50 g of silica gel with 60% ether/ petroleum ether afforded pure samples of each of the sulfoxides. The nnr e n~bile isomer (Isomer A, Rf 22 =0.21 , 30% ether/petroleum ether, 523 mg) was characterized by the following spectral data: NMR (CDC1 3 ) ol.17 (s, 3H , CH 3 ) , 1.9 (m, 2H, =CCH 2 -) , 2.60 (d, 11-1, J=7 Hz, C-3 H), 2.88 (d, lH, J=6 Hz, C-3 H), 3.60 (s, 3H, CH 3 0), 5. 43 (m , 2H, CH=CH), 7.48 (s, SH, C6 H5 ) ; ir (CHC1 3 ) 1720 (C = 0), 1370, 1080, 1035 , 970 The less mobile isomer (Isomer B, Rf 22 =0 .12, 30% ether/petroleum ether, 144 mg) was characterized by the following spectral data : 94 NMR (CDC1 3 ) ol.38 (s, 3H, G-:l 3 ), 1.9 (m, 2H, =CCH 2 -), 2.37 (d, lH, J=7 Hz, C-3 H), 2.60 (d, lH, J=6 Hz, C-3 H), 3.63 (s, SH, C6 H5 ) ; ir (CHC1 3 ) 1725 (C = 0), 1375, 1085, 1045, 975, 910 an- 1 • Each sulfoxide was heated in carbon tetrachloride at 60° for 2 hr. The products were isolated as described above and analyzed by VPC 22 (200°, 1/4 in x 8 ft 10% Carbowax 20 M, 60 ml/min, thermocouple). The following results were obtained. Sulfoxide il/11 Yield of Olef ins Isomer A (High Rf) Isomer B (Low Rf) Original Mixture 68/32 90/10 78/22 99% from Sulfoxide 97% " 93% from ester 40 II ~ Methyl 4,5-Epoxy-2-methyl-2-decenoate (46). The Wl.Saturated ester 41 (3.1 g, 15.8 nnnol) was dissolved in 100 ml of chloroform and 40 mg of 3-tert.-butyl-4-hydroxy-5-methylphenyl sulfide, 27 a free radical inhibitor, was added. To this solution was added 4.02 g (19.8 ITUilOl) of 85% ~-chloroperbenzoic acid and the resulting solution was stirred at 25° for 6 hr. Ether extraction, 23 including a base wash and a 10% aqueous sodium bisulfite wash, gave the crude epoxy ester 46 which was purified by medium-pressure chromatography 22 on .AA. 2.5 x SO an silica gel with 10% ether/petroleum ether at a flow rate of 2.7 ml/min. After elution with 560 ml of this solvent mixture, continued elution with 300ml afforded 3.0 g (90%) of the epoxy ester 46 as a colorless oil. An analytical sample was prepared by evaporative distillation at 70° (0.1 nnn): NMR (CDC1 3 ) 60.5-1.7 (llH), 95 1.98 (d, 3H, J=l.5 Hz, C-2 CH 3 ) , 2.88 (m, lH, C-5 H), 3.33 (dcl, lH, J=2 and 8 Hz, C-4 H), 3.75 (s, 3H, CH 3 0-), 6.30 (br d, lH, J=8 Hz, C-3 H); ir (CHC1 3 ) 1715 (C = 0), 1655 (C = C), 1435, 1315, 1260, 1160, 1105, 915, 870 cm -I . Anal. Calcd for C12 H20 0 3 : C, 67.89; H, 9.50. Foi.md: C, 67.84; H, 9.42. Methyl (E)-5-Hydroxy-2-methyl-3-decenoate (47). A mixture of 24 ml of dry TI-IF and 96 ml of dry anunonia was cooled to -78°. To this stirred solution was added 63 mg (9 rrnnol) of lithium wire in 6 pieces. This solution was stirred for 10 min at -78° and then 636 mg (3.0 mmol) of epoxy ester 46 in 2 ml of 1lfF was added in one portion. The blue """ color persisted for 1 min at which time it was discharged by addition of 9 g of solid anunonium chloride. After an additional 2 min at -78°, the cooling bath was removed, 75 ml of hexane was cautiously added to the reaction mixture, and the ammonia was allowed to evaporate over 4 hr. Ether extraction 23 gave 595 mg of a colorless oil which was purified by chromatography on 50 g of silica gel with 40% ether/ petroleum ether. After elution with 80 ml of this solvent system, continued elution with 20 ml gave 26 mg (4%) of a minor isomer which - was tentatively assigned Z-stereochemistry of ester 47. An analytical sample was prepared by evaporative distillation at 90° (0.05 mm): NMR (CDC1 3 ) 60.9-1.5 (12H), 1.97 (m, 2H, C-6 H's), 2.5 (m, 2H, C-2 H and OH) , 3.68 (s, 3H, CH 3 0-), 4.28 (m, lH, C-5 H), 5.57 (m, 2H, C-3 H and C-4 H); ir (CHC1 3 ) 3600-3400 (OH)~ 1725 (C = 0), 1455, 1005, 970 cm -I . 96 Anal. Calcd for C12 H22 0 3 : C, 67.26; H, 10.35. Found: C, 67.36; H, 10.32. After elution with an additional 10 ml of the same solvent system, continued elution with 85 ml gave 440 mg (69%) of the major ~-isomer .,.,.,. 47 . An analytical sample was prepared by evaporative distillation at 90° (0.05 nun): NMR (COC1 3 ) o0.5-1.9 (15H), 3.13 (m, lH, C-2 H), 3.68 (s, 3H, CH 3 0-), 4.07 (m, lH, C-5 H), 5.67 (m, 2H, C-3 H and C-4 H); ir (CHC1 3 ) 3600 and 3550-3400 (OH), 1725 (C = 0), 1455, 1045, 970 cm- 1 • Anal. Calcd for C12 H22 0 3 : C, 67.26; H, 10.35. found: C, 67.22; H, 10.30. Attempted Hydrolysis of Hydroxy Ester 47. A solution of 140 mg (0.654 nunol) of epoxy ester .....,.. 44 and 157 mg (6.54 nunol) of lithium hydroxide 28 in 4.7 ml of methanol and 1.6 ml of water was stirred at 25° for 2.5 hr. After dilution with water and acidification with cone hydrochloric acid, ether extraction 23 gave 129 mg (99%) of a nearly colorless oil. TLC 22 analysis (ether) indicated that this consisted of two acid components, the more mobile of which quenched fluoresence. An ether solution of 32 mg of this material was treated with excess diazomethane 29 for 20 min at 0°. The excess diazomethane was destroyed by dropwise addition of acetic acid after which ether extraction 23 gave 33 mg of a colorless oil. This material showed only one spot by TLC analysis (50% ether/petroleum ether). Purification was accomplished by medium-pressure chromatography 22 on 0.9 x 60 cm silica gel with ether at a flow rate of 0.5 ml/min. After elution with 26 ml of this solvent, continued elution with an additional 14 ml alfonJc<l :)! rni~ ('Jl '!.) or ;1 97 colorless oil. NMR analysis indicated that this consisted of 70% of ester~ ~3.68 (s, CH 30] and 30% of another methyl ester [?3.73 (s, o-f 3 0) and 6.90 (br t, J=7 Hz, vinylic HJ which was tentatively assigned the structure of the methyl ester arising from conjugated acid 49. -""' Similar results were obtained when the saponification was attempted with potassil.Uil hydroxide in methanol. (E_,§_r2-J\1ethyl-2,4-decadienoic Acid (43). A mixture of 3.0 g and 1.5 g of potassium hydroxide (15.3 rrnnol) of the methyl ester 41 JAA. in 10 ml of methanol was stirred at reflux for 1.5 hr. The reaction mixture was then diluted with 100 ml of water and extracted with two 50-rnl portions of ether (extracts discarded). After acidification of the basic solution with cone hydrochloric acid, ether extraction 23 The gave 2.76 g (99%) of the acid 43 as white crystals, mp 53-56°. ~ analytical sample was prepared by two recrystallizations of this material from petrolel.Uil ether at -20°: NMR (CDC1 3 ) 60.6-1.8 (9H), 1.93 (br s, 3H, C-2 CH 3 ), 2.2 (m, 2H, C6 H5 ), 6.2 (m, 2H, C-4 Hand C-5 H), 7.3 (d, lH, J=lO Hz, C-3 H), 11.0 (br s, lH, C0 2 H); ir (CHC1 3 ) 3500-2500 (C0 H), 1680 (C=O), 1630 (C=C), 1250, 1035, 970 cm- 1 . 2 Anal. Calcd for C11 H18 0 2 : C, 72.49; H, 9.95. Foillld: C, 72.34; H, 9.75. 9-Carbarnoyl-2-methoxy-2-nonenyl (E)-4,5-Epoxy-2-methyl-3- 7 • decenoate 1.,50). A. E_-Nitrophenyl 2-Methyl-2,4-Decadienoate (44). A solution of 2.65 g (14.56 rrnnol) of unsaturated acid 43 in 20 ml of dry triethylarnine """" 98 was cooled to 0°. To this solution was added 3.42 (14.56 rrnnol) of E_-nitrophenyl trifluoroacetate 11 in one portion. This homogeneous solution was stirred at 0° for 30 min , during which an orange lower layer separated. Stirring was then continued for 3 hr at room Ether extraction , 23 including a base wash and a 20% temperature. aqueous monosodilnn phosphate wash, gave an orange oil which was passed through 50 g of silica gel with 300 ml of dichloromethane. This afforded 3.8 g (86%) of the E_-nitrophenyl ester 1i as a slightly yellow oil: NMR (CDC1 3) 60 . 6-1 . 6 (9H) , 2. 07 (br s, 3H, C-2 CH 3), 2.2 (m, 2H, C-6 H's), 6.3 (m, 2H, C-4 Hand C-5 H), 7.32 (d, 2H, J=9 Hz, aromatic), 8.28 (d, 2H, J=9 Hz, aromatic). B. E_-Nitrophenyl 4,5-Epoxy-2-methyl-2-decenoate (45). The - E_-nitrophenyl ester 44 (3.8 g, 12 . 54 rrnnol) was dissolved in 100 ml of chloroform. To this solution was added 3.19 g (15.68 rrnnol) of 85% ~-chloroperbenzoic acid and 40 mg of 3-tert.-butyl-4-hydroxy-5methylphenyl sulfide. 27 This mixture was stirred for 2 hr at 25° and for 2 hr at reflux. Ether extraction, 23 including a 10% aqueous sodil.Ill1 bisulfite wash and a base wash, followed by passage of the residue through 40 g of silica gel with 240 ml of dichloromethane,gave 3.55 g (89%) of the epoxy ester 45 ........ as a slightly yellow oil: NMR (CDCl 3) 60.5-1.9 (llH), 2.13 (d , 3H, J -1.5 Hz, C-2 CH3), 3.0 (m, lH, C-5 H), 3.45 (dd, lH, J=2 and 8 Hz, C-4 H), 6.60 (br d, lH, J=9 Hz, C-3 H), 7.30 (d, 2H, J=9 Hz, aromatic), 8. 30 (d, 2H, J=9 Hz, aromatic) . 99 C. Preparation of Ester SO. A solution of 1.76 g (8.2 rrunol) of the hydroxyamide 22a and 2.62 g (8.2 rrunol) of the ..e_-nitrophenyl ester ~ 0 4S _. in S ml of dry TI-IF and S ml of dry triethylamine was stirred at so for S7 hr. Extraction 23 with 30% dichloromethane/ether, including a base wash, gave 3.2 g of an orange semi-solid. This material was purified by medium-pressure chromatography 22 on 2.S x SO cm of silica gel with 30% acetone/ether at a flow rate of 2 ml/min . After elution with 300 ml of this solvent system, continued elution with 240 ml gave - 2.17 g (67%) of the epoxy ester SO as a nearly colorless oil which solidified upon standing. A portion of this waxy solid was dried at reduced pressure to provide the analytical sample: NMR (COC1) 3 oO. S-1. 9 (19H), 2.02 (s, 3H, vinylic CH), 2.10 (m , 411, =CCH 2 C- and C!_!:iCONH 2 ) , 2.8 (m, lH, C-S H, epoxide), 3. 33 (d<l, lH, J=2 and 8 Hz, C-4 H, epoxide), 3.SO and 3.60 (s, 3H total, Cl-1 3 0-), 4.62 and 4.65 (s, 2H total, =CCH 2 0-), 5.S (br, 2H, NH 2 ) , 6.30 (br d, HI, .J=8 Hz, CH=C-C0 2 -); ir (CHC1 3 ) 3530, 3490 and 3400 (NH 2 ) , 1710 (C = 0, ester), 1675 (C = 0, amide), 1590, 1310, 1155, 870 cm - 1 . Anal. Calcd. for C22H37N0 5 : C, 66.81; H, 9.43; N, 3.54. Found: C, 66.90; H, 9.48; N, 3.49. 9-Carbamoyl-2-methoxy-2-nonenyl 5-Hydroxy-2-methyl-3-decenoate (51). A mixture of 24 ml of dry 1HF and 96 ml of dry anunonia was cooled to -78°. To this stirred solution was added 21 mg (3 rrunol) of lithiwn wire in 3 pieces. This solution was stirred for 10 min at -78°, after which 395 mg (1 rrunol) of the epoxy ester .,,,.,., SO in 2 ml of dry TI-IF was added in one portion. The blue color persisted for 1 min after which it was discharged by addition of 9 g of solid amnonium chloride. After 100 an additional 2 min at -78°, the cooling bath was removed and the arrnnonia was allowed to evaporate over 4.5 hr. Dichloromethane extraction 23 gave 345 mg of a yellow oil which was purified by mediurnpressure chromatography 22 on 1. 25 x 50 cm of silica gel with 30% acetone/ ether. After elution with 110 ml of this solvent system, continued elution with 75 ml afforded 290 mg (73%) of the hydroxy ester 51. A AA. portion of this material was dried at reduced pressure to provide the analytical sample: NMR (CDC1 3 ) 60.5-1.9 (22H), 2.08 (m, 4H, =CCH 2 C- and C!:!_2 CONH 2 ), 3.1 (m, lH, -CHC0 2 -), 3.50 and 3.57 (s, 3H total, CH 3 0-), 4.05 (m, lH, -OiOH), 4.53 and 4.60 (s, 2H total, =CCH 2 0-), 5.63 (m, 4H, CH=CH and NH2); ir (CHC1 3 ) 3600-3250 (OH and NH 2 ), 1725 (C = 0, ester), 1675 (C = 0, amide), 1590, 1460, 970, 915 cm- 1 Anal. Calcd for C22 H39 N0 5 : C, 66.47; H, 9.89: N, 3.52. Found: C, 66.44; H, 9. 76; N, 3.45. 4-(6-Carboxyhexyl)-3-(3-hydroxyoctenyl)-5-methoxy-3,5-dimethyloxacrclopentan-2-one (5~. A solution of 1HF was cooled to -78°. 2. 78 rrnnol of LDA in 10 ml of dry Following addition of 2.4 ml of dry HMPA, 285 mg (0.718 mmol) of the ester 51 .,,.,._ in 2 ml of 1HF was added dropwise over 4 min to the rapidly stirred solution. After an additional 2 min at -78°, 0.840 ml (2.87 JllllX)l) of TBSCl in hexane was added in one portion and stirring was continued for 2 min at -78°. The cooling bath was removed and the reaction mixture was allowed to warm to 25°, after which the mixture was stirred at reflux for 3 hr. Extraction 23 with 75% ether/petroleum ether gave 508 mg of a yellow oil. This material was 101 stirred at reflux with 1.2 g of sodium hydroxide in 6 ml of water and 15 ml of methanol for 16 hr. After dilution with water, the reaction mixture was extracted with two 50 ml portions of ether (extracts discarded) and then acidified by addition of 80 ml of 0.4 N sulfuric acid to the ice-cooled, stirred solution. gave 237 mg of a brown semi-solid. Dichloromethane extraction 23 This was purified by medium-pressure chromatography 22 on 1.25 x 50 cm of silica gel with petroleum ether dichloromethane : 1HF : acetic acid= 50:10:3:2. Following elution with 40 ml of this solvent system, continued elution with 10 ml gave 40 mg of the unsaturated acid 41. Continued elution with 40 ml gave .-.. 44 mg of material which was tentatively identified as the tert.-butyl- - dimethylsilyl ether of the desired lactone 52: NMR (CDC1 3 ) 80.07 3.37 (s, 3H, CH 3 0-), 4.07 (m, lH, CHOSi), 5.63 (m, 2H, CH=CH). After elution with an additional 295 ml of the same solvent system, continued elution with 200 ml gave 65 mg (30%) of the desired lactone-acid 52 as a colorless oil. A portion of this material was v.- dried at reduced pressure and provided the analytical sample: NMR (CDC1 3 ) 80.6-2.0 (28H), 2.3 (m, 2H, CH2C0 2-), 3.36 (s, 3H, CH 3 0), 4.12 (m, lH, -C!:!-OH), 5.7 (m, 2H, CH=CH), 6.2 (br, 2H, OH and C02H); ir (CHC1 3 ) 3600-3400 (OH), 3200-2600 (C0 2H), 1760 (C = 0, lactone), 1710 (C = 0, acid), 1380, 1030, 970, 910 cm Anal. Calcd for C22 H38 0 6 : H, 9.67. - l . C, 66.30, H, 9.61. Found: C, 66.52; 102 References • and rw Notes ,,,, • • (1) (a) Grateful acknowledgement is made for support of this work by the National Science Foundation and the National Institutes of Health. (b) National Science Foundation Predoctoral Fellow, 1972-75. (2) R. E. Ireland and R.H. Mueller, J. Arner. Chern. Soc . , 94, 5897 (1972) . ,._ (3) R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Arner. Chern. Soc., - 98, ,.,,.. 0000 (1976). (4) W. Grell and H. Machleidt, Ann. Chern., 699, 53 (1966). (5) E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, J. Arner. Chem . Soc., 91, 5675 (1969); J. Schmidlin and A. Wettstein , Helv . Chim. Acta, 46 ,"'1799 (1963); G. Saucy and R. Borer , Helv. Chim. Acta, 54, 21!i (1972). (6) D. P. Strike and H. Smith, Tetrahedron Lett . , 4393 (1970). (7) G. Stork, G. L. Nelson, F. Rouessac, and 0. Gringore, J. Arner. Chem. Soc., 93, 3091 (1971). (8) R. A. Ellison, Synthesis, 397 (1973). (9) M. Ohno, N. Naruse, and I. Terasawa, Org . Synthesis, Coll. Vol. 5, - - - 266 (1973) . """ (10) H. C. Brown, "Hydroboration", W. A. Benjamin, Inc . , New York , 1962, p . 245. (11) S. Sakakibara and N. Inukai, Bull. Chern. Soc., Japan, 37, 1231 (1964). .-. (12) D.S. Watt, Syn. Comnrun., 4, 127 (1974). (13) M. W. Rathke and D. F. Sullivan, Syn. Comnrun., 3, 67 (1973). (14) P. M. Mccurry, Jr. and K. Abe, Tetrahedron Lett., 1387 (1974). (15) P. L. Stotter and J.B. Eppner, Tetrahedron Lett . , 2417 (1973); G. A. Koppel, Tetrahedron Lett., 1507 (1972). (16) H. Norrnant , Angew. Chern. Intern. Ed. Eng., 6, 1046 (1967); Bull. """ -Soc. Chim. Fr., 791 (1968). - o'\O 103 (17) K. W. Bowers, R. W. Giese, J. Grimshaw, H. 0. House, N. H. Kolodny, K. Kronberger, and D. K. Roe, J. Amer. Chem. Soc., 92, 2783 (1970); H. 0. House, R. W. Giese, K. Kronberger, 1': P. Kaplan, and J. F. Simeone, J. Amer. Chem. Soc., 92, 2800 (1970). -- (18) E. J. Corey and A. Venkateswarlu, J. Amer. Chem. Soc., 94, 6190 (1972). (19) L. J. Bellamy, "The Infra-red Spectra of Complex r.blecules", John Wiley and Sons, New York, 1956, pp. 40-42. (20) B. M. Trost and T. N. Salzmann, J. Amer. Chem. Soc., 95, 6840 (1973). - (21) E. J. Corey, C. S. Shiner, R. P. Volante, and C. R. Cyr, Tetrahedron Lett., 1161 (1975). (22) Boiling points are uncorrected. Infrared (ir) spectra were determined on a Perkin-Elmer 237B grating infrared spectrometer and nuclear magnetic resonance (NMR) spectra were recorded using a Varian T-60 spectrometer. Chemical shifts are reported as o values in parts per million relative to 'IMS (o 'IMS = 0.0 ppm) as an internal standard. Deuteriochloroform for NMR and chloroform for ir spectra were filtered through neutral alumina before use. Vapor phase chromatographic (VPC) analyses were determined on either a Hewlett-Packard 5750 equipped with a flame ionization detector or a Varian 920 equipped with a thermal conductivity detector using helium as the carrier gas under the i ndicated conditions. The indicated liquid phase was absorbed on 60-80 mesh Chromosorb WAW IMCS. Silica gel columns used the 0.05-0.2 mm silica gel manufactured by E. Merck &Co., Dannstadt, Germany. Acidic silica gel re f ers to Silicar CC-4 Special "For Column Chromatography", sold by Mallinckrodt Chemical Works, St. Louis, Missouri. Preparative medium-pressure chromatography was performed using glass columns of the indicated length and diameter with fittings supplied by Laboratory Data Control, Riviera Beach, Fla., and an instTlUilent minipump supplied by Milton Roy Co., St. Petersburg, Florida (instTlUilentation designed by R. H. Mueller, these laboratories, and copies are available on request). The columns were packed with silica gel H "for TLC acc. to Stahl" (10-40 µ) manufactur ed by E. Merck &Co., Dannstadt, Germany. Solvents were degass ed under water aspirator vacuum prior to use. Analytical thin layer chromatography was conducted on 2.5 x 10 cm Pre-coated TLC Plates, Silica Gel 60 F-254, layer thickness 0.25 mm manufactured by E. Merck &Co., Dannstadt, Germany. 104 (22) continued: "Dry" solvents were dried innnediately prior to use. Ether and tetrahydrofuran (TI-IF) were distilled from lithium aluminum hydride; pyridine, triethylamine, diisopropylamine, N-isopropylcyclohexylamine, trimethylchlorosilane (1MSC1), hexaffiethylphos phoramide (HMPA), benzene, and toluene were distilled from calcium hydride; dimethylformamide (DMF) was dried over 4 A molecular sieves and fractionally distilled at reduced pressure; methanol was dried over 3 A molecular sieves; annnonia was dist i lled from a blue solution of sodium directly into the reaction flask; dichloromethane, methyl iodide, and hexane were distilled from phosphorous pentoxide. "Petroleum ether" refers to the "Analyzed Reagent" grade hydrocarbon fraction, bp 30-60°, which is supplied by J. T. Baker Co., Phillipsburg, N. J., and was not further purified. Diisobutylaluminum hydride (DIBAH) was used as a standard soluti on in benzene (ca. 1.0 M). Lithium isopropylcyclohexylamide (LICA) and lithium diisopropyl amide (LDA) were prepared as described previously . 3 Standard solutions of tert.-butyldimethylchlorosilane (TBSCl) in hexane (ca . 3.3 M) or HMPA (ca. 1.5 M) were employed. Reactions were run under an argon atmosphere arranged with a mercury bubbler so that the system could be alternately evacuated and filled with argon and left under a posit i ve pressure . Microanalyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Michigan. (23) In cases where the products were isolated "by solvent extraction" , the procedure generally followed was to dilute the reaction mixture with the indicated solvent or to extract the aqueous solution with several portions of the indicated solvent; then the combined organic layers were washed with several portions of water followed by saturated brine. The organic layer was dried over anhydrous sodium or magnesium sulfate, then filt ered, and the solvent was evaporated from the filtrate under reduced pressure (water aspirator) using a rotary evaporator. The use of the terms "base wash" or "acid wash" indicate washing the organic solution with saturated aqueous sodium bicarbonate solution or with dilute aqueous hydrochloric acid, respectively prior to the aforementioned wash with water. 105 (24) · L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis" , John Wiley and Sons, Inc., New York, 1967, p. 584. (25) M. Gouge, Arm . chim . , 6, 648 (1951). (26) N. H. Anderson, J. Lipid Res., 10, 316 (1969). (27) Y. Kishi, M. Aratani, H. Tanino, T. Fukuyama, T. Goto, s. Inoue , s. Sugiura, H. Kakoi, J.C. S. Chem. Cormn., 64 (1972). (28) E. Andre and J. Henry, Compt. rend., 263, 1084 (1966). (29) H. M. Fales, T. M. Jaouni, and J. F. Babashak, Anal. Chem., 45, 2302 (1973). • - - - - 106 PROPOSITIONS 107 Abstract of Propositions proQQSi.lion 1: Promotion of regioselective and stereoselective enolization of ketones and esters by means of a carboxylate ligand on the substrate molecule is proposed. Examples of stereoselective enolization of a,B-unsaturated esters and acids are cited. This selectivity can be traced to association of the lithium dialkylamide base with the carboxylate prior to proton removal. A series of molecules designed to test the generality of this selective enolization is suggested. ~s.hiQD .Z: An investigation of the reactions of N._alkylpyridinium salts and pyridine-N-oxides with organocuprate reagents is proposed. An electron transfer mechanism for organocuprate reactions is assumed. The reduction potential of the above N-substitute<l pyrid ine derivatives is within the range to make them potential substrates. Alkyl substituted 1,2- or 1,4-dihydropyridines are the expected products . These derivatives are potentially valuable intermediates for organic synthesis. Proposition 3: The catalytic involvement of chiral crown ethers and cryptands in asynnnetric synthesis is proposed. These ligands form stable complexes with metal cations and should impart chirality to associated achiral anions. Reaction with electrophiles should result in asynnnetric induction catalyzed by the chiral ligand. Two basic types of reactions are suggested. PropQsition 4: Heterocyclic oxyselenation of olefins is proposed. Electrophilic reactions of reagents of the type PhSe-X with olef ins are examined and the extension of these reactions to olefinic substrates which contain an intramolecular nucleophile is suggested. Lactonizat i on , the simplest example, should lead to lactones with the phenylseleno functional group attached as a handle for further synthetic trans formations . ProQQ_si!ion 5: The preparation of a series of compounds whose chemistry should provide useful information for construction of "synthetic enzymes" is proposed. TI1e chemistry of a series of molecules containing rnacropolycyclic ligands (cryptands) covalently attached to an organic functional group would be examined. The combination of "anion activation" by the ligand and juxtaposition of a reactive functional group should result in novel chemistry. Information gained should be useful for the ultimate preparation of molecular catalysts capable of promoting specific reactions on organic substrates. 108 Proposition .!_ Promotion of regioselective and stereoselective enolization of ketones and esters by means of a carboxylate ligand on the substrate molecule is proposed. At least three unheralded instances of selective, kinetic enolization of a,8-unsaturated esters have been reported. The stereo- chemical composition of the products in the synthesis of juvenile hormone analogs by Frater 1 can be traced back to the stereoselective ,,. enolization depicted in Eq. 1. Frater also noted the apparent preference for proton removal from the alkyl group cis to the ester functionality (Eq. 2). Pfeffer and Silbert 2 demonstrated that decon- jugation of a,8 -unsaturated acids via protonation of the dianion formed with lithilllll diisopropylamide produced exclusively trans-double bonds from cis-acids but a mixture from trans-acids (Eq. 3). OR ~- (1) 85% OR OR JC 15% ... (2) stereochernistry unknown Gl3 109 (3) All of these results can be rationalized by a mechanism which involves coordination of the lithium dialkyl amide base with the carbonyl oxygen of the carboxylate or the ester prior to proton removal . The scope and limitations of this selectivity with a ,B-unsaturated esters should be examined . It should be possible to ext end these results to regioselective enolization of ketones. Eqs . 4 - 6 depict systems worthy of examination. (4) (5) If the reliability of selective enolization can be demonstrated, a useful new tool for directed synthesis will be available. References: 1. G. Frater, Helv. Chim. Acta,~' 442 (1975). 2. P. E. Pfeffer and L. S. Silbert, J. Org. Chem.,.}§., 3290 (1971). 111 Proposition ~ An investigation of the reactions of !i_-alkylpyridinitnn salts and pyridine-!i_-oxides with organocuprate reagents is proposed. Beyond its obvious role in the preparation of a variety of nitrogen heterocycles, the pyridine nucleus has not been heavily exploited by synthetic chemists . Two examples from carbocyclic chemistry serve to demonstrate its potential (Eqs. 1 and 2). (1) Ref. 2 (2) Both of these cyclohexenone products arise via metal-anunonia reduc tion to a 1 , 4-dihydropyridine. An alternative approach to the dihydro- pyridines might be by reaction with organocuprate reagents (R 2 CuLi) , a transformation which M:>uld couple the reduction with attachment of an alkyl group to the pyridine nucleus (Eq. 3). 112 R 0 ~ N 0 I x 6 /I y (3) ~D R N I y All reactions of the organocuprate reagents can be accounted for by a mechanism in which electron transfer is the first step. 3 ,1+ This suggests that the reduction potential of the substrate molecule is important. In fact, in the reaction of organocuprates with enones , only those enones with a reduction potential less negative than -2.4 V vs SCE react. 3 Limited evidence suggests that this is also true for other substrates . Pyridine (E 1; 2 = -2.61 V vs SCE) does not react with lithiwn dimethylcuprate . !i-Alkylpyridinit.nn salts (El/Z = pyridine-!i-oxides (El/ 2 = ca. -1. 4 V) should react. ca. -1.0 V) and Whether these substrates go on to give alkylated products after electron trans fer and whether these products are 2- or 4-substituted dihy<lropyri<line derivatives can't be answered at this point . Investigation of the reaction of these two pyridine derivatives with organocuprates has two values. First, the results with these substrates have important bearing on the mechanism of organocuprate reaction and should suggest or rule out other substrates. Second, the 113 resulting dihydropyridines (should the reaction take this course) will be useful synthetic intennediates and will expand the potential of pyridine derivatives in organic synthesis. References: 1. A. J . Birch, J. Chern. Soc., 1270 (1947). 2. S. Danishefsky and R. Cavanaugh, J. Arner. Chem. Soc., 90, 520 (19680. 3. H. 0 . House and M. J. lhnen, J. Amer. Chern. Soc., 94, 5495 (1972). 4. D. J. Hannah and R. A. J. Smith, Tetrahedron Lett., 187 (1975). 114 Proposition l The catalytic involvement of chiral crown ethers and cryptands in asynunetric synthesis is proposed. Asynunetric synthesis has been defined as "a reaction in which an achiral llllit in an ensemble of substrate molecules is converted by a reactant into a chiral llllit in such a manner that the stereoisorneric products are produced in llllequal arnollllts." 1 Practicality demands efficient use of the chiral reagents in these reactions; chiral catalysts represent the ultimate in efficiency. Chiral crown ethers 2 such as ..l and chiral cryptands 3 such as J_ are now available. These ligands form stable complexes with alkali and alkaline-earth metal cations and this complexation imparts chirality to the associated achiral anion. Since interaction of the ligand with the cation is through ion-dipole and related interactions but not covalent bonds, and because the ligand can be recovered unchanged, the ligand is playing a truly catalylic role. ro~ ~ ) ~ o~ r.N~ 0 $ 1-_~J) ........... C0 2 H .l. 0 1.. 115 These ligands can be expected t o promote asynnnetric synthesis in two types of reactions . In the first, the substrate reacts with a complexed, nucleophilic reactant. Exampl es are hydride reduct i on of ketones (Eq. 1), alkyllithitnn additions t o carbonyl compounds, and nucleophilic additions to activated double bonds. In the second type, the substrate is complexed and reaction with an electrophilic reactant produces the chiral unit. Alkylation of metallo-imincs, aldol conden- sations , and alkylations of enolates (Eq. 2) are examples. + (R0) 3AlH Li·Ligand H X.. OH * ... + (1) R H\ . _ /0- Li Ligand * 0 I \R,. R R,. ,. • H 11 R,. 0 ,)-~ R R,. + R,.,._X This chir al catalysis can be expanded through construction of specifically designed ligands to optimize the degree of asynunetric induction. Ligand design will also effect kinetics and thennodynamics of complexation which will control such variables as turnover ntnnber. Ultimately, the most effective catalysts may be those which have (2) 116 chiral cavities large enough to contain both the substrate and the reactant in specific orientations. References: 1. J. D. MJrrison and H. S. lt>sher, "Asynunetric Organic Reactions ," Prentice-Hall, Englewood Cliffs, New Jersey , 1971. 2. R. C. Helgeson, K. Koga, J. M. Timko and 0. J. Cram, J . Arner. Chem. Soc . , 95, 3021 (1975) . -3. --- B. Dietrich, J.- M. Lehn and J. Simon, Angew. Chem. Internat . Ed. Eng., !.2,, 406 (1974). 117 Proposition _! Heterocyclic oxyselenation of olefins is proposed. Electrophilic addition of reagents of the type PhSe-X (X =Cl, Br, RC0 2 -) across carbon-carbon double bonds 1 ' 2 has great potential in organic synthesis. This addition is mechanistically similar to other electrophilic additions but offers the advantage that the phenylseleno function is a useful handle on the molecule for further synthetic transformations. For instance, oxidation to the selenoxide followed by elimination introduces a double bond. It should be possible to extend these reactions to cases in which the nucleophilic partner in the addition is part of the substrate molecule. The simplest example would be lactone formation with electro- philic organoselenium reagents. (see Scheme) There are two possible pathways for formation of the lactone. Either direct attact by the carboxylate on the episelenonium ion (or its equivalent) or addition of PhSe-X to the olefi n followed by solvolytic displacement of X by the carboxylate could result in lactonization. The propensity to form 5- rather than 6-membered rings, as is noted for other lactonization procedures, will probably be found in this case also. Results with the simple acyclic cases suggest that elimi- nation of the selenoxide should produce allylic rather than vinylic derivatives whenever possible. Several experimental procedures will have reasonable chances for success in this lactonization. Addition of potassiwn acetate to a 118 Scheme: 0 0 OH OH R R x Se Ph ePh 0 0 x 0 R • or x 0 OH Se Ph R 0 or R,. or + HX DSePh 0 0 R 0 R 119 mixture of PhSeBr and an olefin in acetic acid produces an acetate. 1 This may be occurring through direct addition of PhSeOAc or by acetolysis of the first-formed PhSeBr adduct. Addition of PhSeBr to the potassium salt of the olefinic acid in a suitable inert solvent should cause lactone formation by one of the above mechanisms. A second possibility lies in the use of benzeneselenyl trifluoroacetate. 2 Trifluoroacetate is a weak nucleophile and may permit direct opening of the episelenoniurn ion by the intrarnolecular carboxylate. has proven useful in oxyrnercuration of olefins. 3 This concept Finally, if lactoni- zation is not realized by the above procedures, silver assisted solvolysis of the PhSeBr adduct should be effective. If this heterocyclic oxyselenation is successful for preparation of lactones, it can probably be extended to the preparation of cyclic ethers and amines. References: 1. K. B. Sharpless and R. F. Lauer, J . Org. Chern., }g, 429 (1974). 2. H.J. Reich, J. Org. Chern., 39, 428 (1974). 3. H. C. Brown and M.-H. Rei, J. Arner. Chern. Soc., 21,, 5646 (1969). 120 Proposition ~ The preparation of a series of compounds whose chemistry should provide useful information for construction of "synthetic enzymes" is proposed. The "crown ethers" and a related family of molecules, polyoxapolyazamacropolycyclic ligands introduced subsequently by J.-M. Lehn, 1 hold promise in many areas of chemistry. Their well-known ability to form stable complexes which should allow metal ion selection and transport has already been heavily explored. 2 More recently, similar ligands capable of complexing organic molecules have been introduced. 3 ,~ Results in both of these areas suggest that it may ultimately be possible to prepare "synthetic enzymes" employing these ligands. Specifically, it is proposed to prepare a series of molecules related to_L (other organic functional groups as well as the ester would be examined) and to study their chemistry, some of which may be anticipated in the scheme. Two effects are brought into play which should lead to interesting chemistry. As a consequence of the ligands forming stable complexes with metal cations, the associated anions become chemically activated and reactive. When this is coupled with the juxtaposition of the substrate by covalent attachment to the ligand, novel results can be cxpectc<l. Information on three points useful in later approaches to synthetic enzymes should be obtained: (1) M:>des of reaction -- The serious geometrical and chemical stresses applied to the systems may lead to deviations 121 from the normal chemistry expected from these reagents . 111e reaction paths can be elucidated by product studies; (2) Reaction rates -- Rate enhancements of several orders of magnitude are found in the reactions of the activated anions fonned in the presence of these ligands. For the proposed molecules, covalent attachment of the substrate to the ligand will make the reaction essentially "intramolecular" causing further dramatic increases in rate; (3) Substrate-reactivity relationships -- Several variables, including the ligand, the cation, the anion, and the reaction medium can be systematically varied to generate highly useful infonnation about the reactivity of these molecules. . Scheme: 0- (CH,)n-~+ R-X 0- ~CH 2 )n-~O+ H-X + R~-CH=CH2 122 The synthesis of the molecules required for the study will be quite straightforward, following essentially the methods described by Lehn. 2 The work described should map a portion of the frontier, putting organic chemists one step closer to acquiring the knowledge required to prepare synthetic molecules capable of mlinicking the important biological enzymes. Such capabilities could revolutionize synthetic chemistry and, even more iJnportantly, medicine. References: 1. (a) B. Dietrich, J.-M. Lehn and J.P. Sauvage, Tetrahedron Lett., 1969, 2885, 2889; (b) J.-M. Lehn and F. MJntavon, Tet rahedron Lett., 1972, 4557. 2. J.-M. Lehn, Structure Bonding (Berlin), 16, 1 (1973) . 3. J.-M. Lehn, J . Slinon and J. Wagner, Ang. Chem. Int. Ed. Eng., 12, 578,579 (1973). 4. D. J. Cram and J.M. Cram , Science, 183, 803 (1974).